Disorders of sexual Development Flashcards
What structure undergoes condensation and shortening to promote descent of the testis?
The gubernaculum anchors the testis to the genital region and condenses to allow descent.
How many attachments does the gubernaculum have and what are they called?
The gubernaculum typically has 5 attachments, which are called slips.
What transcription factor is associated with testicular descent from the abdominal cavity to the inguinal canal (transabdominal)?
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.
What transcription factor is critical for gonadal differentiation toward the male lineage?
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.
What happens if the TDF (testis determining factor) is not expressed or mutated in a genotypic male (46 XY)?
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.
At what time point in fetal development does the gonad differentiate to become a testis or ovary?
Between the 6th to 8th week of gestation, the indifferent (bipotential) gonad differentiates into either a testis or an ovary.
What cell type is responsible for producing MIS?
The fetal Sertoli cells produce MIS.
What soluble factor superfamily does MIS belong to?
Transforming growth factor beta (TGFβ).
Which active steroid hormone is important for Wolffian duct induction and proliferation?
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.
What enzyme converts testosterone into dihydrotestosterone (DHT)?
The conversion is mediated by 5-alpha-reductase.
How does DHT influence male sexual development?
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.
MIS suppresses the development of which female reproductive structures?
MIS prevents the development of the oviduct, uterus, cervix, and upper third of the vagina.
What is the most common cause of disorders of sexual development (DSD) in children in North America and Europe and how common is it?
The most common cause is Klinefelter syndrome (incidence in the United States is approximately 1:500 live births).
What physical findings are most suggestive of disorders of sexual development (DSD)?
Ambiguous genitalia; nonpalpable gonads and severe hypospadias.
What laboratory tests are most often used to confirm the presence of congenital adrenal hyperplasia?
The most appropriate tests include fluorescence in situ hybridization (FISH) or karyotype analysis, and plasma 17-hydroxyprogesterone >500 mg/DL.
What are the two most common enzyme defects resulting in congenital adrenal hyperplasia?
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.
What imaging studies are the most helpful in defining the anatomy associated with a DSD?
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.
What is the typical appearance of a patient with complete androgen insensitivity syndrome (CAIS) and why?
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.
What is the typical development of the internal genitalia in patients with CAIS?
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.
What is the most common demonstrable defect seen in patients with CAIS?
The most common finding is the absence of high-affinity binding of DHT.
What are the common clinical presentations that most often lead to the diagnosis of CAIS?
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.
What is the most common karyotype in patients with ovotesticular DSD (true hermaphroditism)?
The most common karyotypic finding is 46XX.
What are the most common gonadal malignancies associated with a dysgenetic gonad and the presence of a Y chromosome?
The most common malignancies are gonadoblastomas and dysgerminomas.
What is the most common karyotypic finding in Klinefelter syndrome?
One additional X chromosome (47, XXY).
What is the histopathologic finding in patients with pure gonadal dysgenesis?
Bilateral streak gonads and underdeveloped Müllerian structures are found.
During development, when does the gonad develop into a testis?
During the second month.
What is anti-Müllerian hormone (AMH)?
AMH is the same as MIS.
True/False: an ovotesticular DSD often has a degree of Wolffian development near the testicular tissue even when joined to an ovary.
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.
The external genitalia of both sexes are identical through how many weeks of gestation?
Seven weeks.
What is the incidence of a DSD condition when two impalpable testes are found on examination?
Fifty percent.
Congenital adrenal hyperplasia is associated with what potentially lethal condition?
Salt-wasting nephropathy occurs in 75%. If not recognized, the resulting hypotension can cause vascular collapse and death.
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?
Isolated deficiency of MIS.
What is the controversy regarding management of CAIS?
Whether or not to leave the gonads in situ until the child completes pubertal development.
