Disorders of sexual Development

Question 1

What structure undergoes condensation and shortening to promote descent of the testis?

Answer 1

The gubernaculum anchors the testis to the genital region and condenses to allow descent.

Question 2

How many attachments does the gubernaculum have and what are they called?

Answer 2

The gubernaculum typically has 5 attachments, which are called slips.

Question 3

What transcription factor is associated with testicular descent from the abdominal cavity to the inguinal canal (transabdominal)?

Answer 3

INSL3 (insulin-like 3) is expressed by testicular Leydig cells. Production of this protein rises in the second trimester of gestation and works in conjunction with testosterone to promote testicular descent.

Question 4

What transcription factor is critical for gonadal differentiation toward the male lineage?

Answer 4

SRY (sex determining region on the short arm of the Y chromosome), also known as the testis determining factor (TDF). SRY directly binds to specific DNA loci and regulates the differentiation of the bipotential gonad toward testicular development. Thus far, the SRY protein is considered the “master switch” that initiates testicular development.

Question 5

What happens if the TDF (testis determining factor) is not expressed or mutated in a genotypic male (46 XY)?

Answer 5

The bipotential gonad differentiates toward the ovarian lineage. Sertoli and Leydig cells do not form; Müllerian inhibiting substance (MIS) and testosterone are not produced. Thus, Müllerian duct development is promoted and Wolffian duct development is suppressed.

Question 6

At what time point in fetal development does the gonad differentiate to become a testis or ovary?

Answer 6

Between the 6th to 8th week of gestation, the indifferent (bipotential) gonad differentiates into either a testis or an ovary.

Question 7

What cell type is responsible for producing MIS?

Answer 7

The fetal Sertoli cells produce MIS.

Question 8

What soluble factor superfamily does MIS belong to?

Answer 8

Transforming growth factor beta (TGFβ).

Question 9

Which active steroid hormone is important for Wolffian duct induction and proliferation?

Answer 9

The presence of testosterone results in the proliferation of the Wolffian duct system and the development of the efferent ductules, rete testis, epididymis, vas deferens, and seminal vesicles.

Question 10

What enzyme converts testosterone into dihydrotestosterone (DHT)?

Answer 10

The conversion is mediated by 5-alpha-reductase.

Question 11

How does DHT influence male sexual development?

Answer 11

DHT is the active form of testosterone that induces virilization of the genitals. DHT influences the elongation of the genital tubercle to form the penis, tubularization of urethra, and fusion of the labioscrotal folds.

Question 12

MIS suppresses the development of which female reproductive structures?

Answer 12

MIS prevents the development of the oviduct, uterus, cervix, and upper third of the vagina.

Question 13

What is the most common cause of disorders of sexual development (DSD) in children in North America and Europe and how common is it?

Answer 13

The most common cause is Klinefelter syndrome (incidence in the United States is approximately 1:500 live births).

Question 14

What physical findings are most suggestive of disorders of sexual development (DSD)?

Answer 14

Ambiguous genitalia; nonpalpable gonads and severe hypospadias.

Question 15

What laboratory tests are most often used to confirm the presence of congenital adrenal hyperplasia?

Answer 15

The most appropriate tests include fluorescence in situ hybridization (FISH) or karyotype analysis, and plasma 17-hydroxyprogesterone >500 mg/DL.

Question 16

What are the two most common enzyme defects resulting in congenital adrenal hyperplasia?

Answer 16

21-hydroxylase deficiency (90% of cases) and 11-beta hydroxylase deficiency (5% of cases). Both enzyme defects result in elevated plasma levels of 17-hydroxyprogesterone. 11-beta hydroxylase deficiency specifically results in elevated plasma levels of 11-deoxycortisol and 11-deoxycorticosterone.

Question 17

What imaging studies are the most helpful in defining the anatomy associated with a DSD?

Answer 17

Use of the abdomino-pelvic ultrasound (to look for the presence of a uterus) and a fluoroscopic genitogram to look for a vaginal connection to the urogenital sinus are extremely helpful.

Question 18

What is the typical appearance of a patient with complete androgen insensitivity syndrome (CAIS) and why?

Answer 18

These patients appear as normal phenotypic females with normal development of secondary sexual characteristics. Development of the external male genitalia does not occur due to the lack of androgen receptor activation.

Question 19

What is the typical development of the internal genitalia in patients with CAIS?

Answer 19

On examination, these patients have a short, blind-ending vagina with no internal Müllerian duct structures. Since MIS is present during embryogenesis, the Müllerian duct structures do not develop.

Question 20

What is the most common demonstrable defect seen in patients with CAIS?

Answer 20

The most common finding is the absence of high-affinity binding of DHT.

Question 21

What are the common clinical presentations that most often lead to the diagnosis of CAIS?

Answer 21

Primary amenorrhea (peripubertal) and female patients with bilateral inguinal hernias. Approximately 2% of females presenting with these findings will have CAIS. Females with clinically significant hernias may benefit from vaginoscopy at the time of surgery to confirm the presence of a cervix.

Question 22

What is the most common karyotype in patients with ovotesticular DSD (true hermaphroditism)?

Answer 22

The most common karyotypic finding is 46XX.

Question 23

What are the most common gonadal malignancies associated with a dysgenetic gonad and the presence of a Y chromosome?

Answer 23

The most common malignancies are gonadoblastomas and dysgerminomas.

Question 24

What is the most common karyotypic finding in Klinefelter syndrome?

Answer 24

One additional X chromosome (47, XXY).

Question 25

What is the histopathologic finding in patients with pure gonadal dysgenesis?

Answer 25

Bilateral streak gonads and underdeveloped Müllerian structures are found.

Question 26

During development, when does the gonad develop into a testis?

Answer 26

During the second month.

Question 27

What is anti-Müllerian hormone (AMH)?

Answer 27

AMH is the same as MIS.

Question 28

True/False: an ovotesticular DSD often has a degree of Wolffian development near the testicular tissue even when joined to an ovary.

Answer 28

True. The gonad contains both ovarian and testicular elements. The paracrine effect of the testicular element on the Wolffian duct results in the development of this tissue to varying degrees.

Question 29

The external genitalia of both sexes are identical through how many weeks of gestation?

Answer 29

Seven weeks.

Question 30

What is the incidence of a DSD condition when two impalpable testes are found on examination?

Answer 30

Fifty percent.

Question 31

Congenital adrenal hyperplasia is associated with what potentially lethal condition?

Answer 31

Salt-wasting nephropathy occurs in 75%. If not recognized, the resulting hypotension can cause vascular collapse and death.

Question 32

A perfectly normal-appearing phenotypic male presents with an inguinal hernia on one side and and impalpable testis on the other. Karyotype is 46XY. What DSD problem is most likely?

Answer 32

Isolated deficiency of MIS.

Question 33

What is the controversy regarding management of CAIS?

Answer 33

Whether or not to leave the gonads in situ until the child completes pubertal development.