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Flashcards in Embryology and CAH Deck (21):
1

What is the key to sexual dimorphism?

The key to sexual dimorphism is the Y chromosome, specifically SRY (sex determining region of Y) which is located on the short arm of the Y chromosome. Starting at 7 weeks, expression of SRY initiates a genetic cascade that causes the indifferent gonad to develop into testes.

2

How do the testes influence the development of the mullerian and wolffian ducts?

Once testicular differentiation has been determined, the fetal testes produce two substances critical for male differentiation of these ducts. Antimüllerian hormone (AMH) promotes the regression of müllerian structures, and high local concentrations of testosterone from the leydig cells of the testes stimulates growth of the wolffian structures. The wolffian structures become the epididymis, vas deferens, and seminal vesicle.

3

What happens to the mullerian and wolffian ducts in the absence of testes?

In the absence of testes, as in an XX fetus, there is no AMH production and so the mullerian stuctures develop into the paired fallopian tubes, the midline uterus, and the upper portion of the vagina. Without high local concentrations of testosterone, the Wollfian structures regress.

4

What are the three embryologic structures that give rise to the external genitalia and what specific parts does each develop into?

Genital tubercle - the penis or clitoris)
Labial-scrotal folds - the scrotum or labia major
Urethral folds - the penile urethra or labia minora

5

What is the definition of DSD?

A Disorder of Sexual Development is incomplete or disordered genital or gonadal development that cause a discordance between genetic sex, gonadal sex, and phenotypic sex.

6

What are the three main processes whose improper function may cause a DSD?

Disorders of sex development stem from alterations in three main processes: gonadal differentiation, steroidogenesis, or androgen action.

7

What laboratory and clinical tests should be done to rule out the possibility of a DSD?

In all infants, FISH studies for “SRY” and either karyotype or chromosomal microarray should be done initially. Additional laboratory evaluation is usually based on these results. A pelvic ultrasound should also be done to evaluate for the presence of a uterus.

8

What is the most common 46, XX DSD?

The most common 46,XX DSD is congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. In the classic salt-losing form of this disorder, infant girls present with genital ambiguity but have normal uterus and ovaries.

9

If a 46, XY DSD results from abnormalities in testicular differentiation and development, what is it termed and what two types exist?

This is referred to as gonadal dysgenesis. Individuals with 46, XY complete gonadal dysgenesis have normal female external genitalia and streak gonads. As there is no AMH or testosterone production, internal reproductive structures are also female. They typically present as girls with delayed puberty and amenorrhea. 46,XY partial gonadal dysgenesis results in incomplete testis determination so there is ambiguous genitalia with varying degrees of virilization.

10

What two critical hormones are produced by the testes, what development do they direct, and what occurs without them?

The testes produce Anti-mullerian Hormone (AMH, or MIF) and testosterone. AMH causes the degeneration of the mullerian (paramesonephric) structures and inhibits the formation of internal genitalia and structures. Testosterone induces the development of the wolffian (mesonephric) structures which become the epididymis, vas deferens, and seminal vesicle. If testes do not develop, the lack of AMH leads to internal genitalia and the lack of testosterone leads to vas deferens, epididymis, and seminal vesicle not forming.

11

Other than disorders of testicular development, what other condition may cause a 46, XY DSD?

46,XY DSD can also result from disorders of steroidogenesis. Since the gonads and adrenal gland share common enzymes of steroid hormone production, some of the enzymatic defects associated with male genital ambiguity may also affect production of cortisol and aldosterone, leading to cortisol deficiency and salt wasting.

12

What causes Complete Androgen Insensitivity Syndrome and what is its inheritance pattern?

Androgen Insensitivity Syndrome (AIS) is caused by mutations in the androgen receptor gene. Complete Androgen Insensitivity Syndrome (CAIS) is an X-linked trait.

13

What are the effects of CAIS and what are the long-term consequences and risks if the condition is not diagnosed early?

In CAIS, there is no or little androgen mediated effects. Affected XY individuals have normal female external genitalia with a short vagina, absence of Mullerian structures (due to production of AMH from testes), and lack of Wolffian structures (due to lack of testosterone effect). Gonads are intraabdominal or in the inguinal canal. If the diagnosis is not made early and the testes remain in place, spontaneous breast development occurs at puberty secondary to the aromatization of testosterone to estrogen. There is little or no pubic and axillary hair. Gonadectomy is generally recommended as gonads left in situ are at risk for malignant degeneration. Individuals with CAIS have normal female gender identity. Partial androgen insensitivity typically is manifested by ambiguous genitalia.

14

How does the hypothalamic-pituitary-adrenal axis influence disorders of virilization with salt wasting?

The hypothalamic-pituitary-adrenal feedback system is mediated through circulating plasma cortisol levels; low cortisol results in increased ACTH secretion. Cortisol therefore exerts a negative feedback effect on ACTH secretion. In most forms of CAH, an enzyme defect results in decreased cortisol production which results in an increase in ACTH secretion. Oversecretion of ACTH results in adrenal hyperplasia and excessive synthesis of adrenal products of those pathways unimpaired by the enzyme deficiency.

15

What is the most common type of CAH?

The most common type of CAH is 21-hydroxylase deficiency which accounts for 95% of CAH cases. In 21-hydroxylase deficiency, the aldosterone and cortisol pathways are blocked and the androgen pathway is overstimulated.

16

What are the clinical manifestations of 21-hydroxylase deficiency?

The clinical manifestations are hyponatremia and hyperkalemia due to aldosterone deficiency and possible hypoglycemia and hypotension from cortisol deficiency. Increased androgen production leads to virilization of the external genitalia in affected females. The internal duct anatomy (uterus, fallopian tubes, and proximal vagina) is not affected since the female lacks testes and therefore lacks local testosterone secretion and antimullerian hormone (AMH). Newborn males with 21-hydroxylase deficiency do not show evidence of excessive virilization, making their diagnosis unapparent without specific screening tests. Both newborn boys and girls with 21-hydroxylase deficiency are subject to early, life-threatening, salt-wasting crises within the first weeks of life.

17

What is the second most common form of CAH?

11β-hydroxylase deficiency is the second most common form of CAH accounting for about 5% of cases. This deficiency results in the accumulation of 11-deoxycorticosterone, a potent mineralocorticoid. Thus, even without aldosterone, salt-retention and frequently hypertension results. Cortisol deficiency is the result of the enzyme block in the Zona Fasciculata, and virilization occurs due to over stimulation of the Zona Reticularis by ACTH.

18

What is Steroidogenic Acute Regulatory Protein and what are the consequences of its deficiency?

StAR (Steroidogenic Acute Regulatory) Protein deficiency is very rare and affects all Zones of the adrenal gland. StAR is involved in the transfer of cholesterol from the outer to inner mitochondrial membrane, the rate-limiting step in steroidogenesis. Cholesterol and cholesterol ester accumulates in the gland causing “lipoid” hyperplasia. As no adrenal products are made, affected males are undervirilized (typically have normal female external genitalia). Both affected females and males have salt-wasting and cortisol deficiency. If undetected, this form of CAH is usually fatal in infancy.

19

What are the consequences of 3β-hydroxysteroid dehydrogenase deficiency?

3β-hydroxysteroid dehydrogenase deficiency results in salt wasting. In males, undervirilization occurs because testosterone production is decreased. In females, however, virilization occurs due to elevated dehydroepiandrosterone.

20

What are the consequences of 17α-hydroxylase/17,20 lyase deficiency?

17α-hydroxylase/17,20 lyase deficiency affects steroid synthesis both in the adrenals and gonads. Patients have cortisol deficiency which leads to elevated ACTH which increases deoxycorticosterone, resulting in salt-retention, hypertension and hypokalemia. Affected males are born undervirilized due to deficient testosterone production. Affected females are born with normal female genitalia but fail to develop secondary sex characteristics at puberty.

21

What are the five primary deficiencies that result in CAH?

21-hydroxylase, 11B-hydroxylase, 3B-hydroxysteroid dehydrogenase, 17a-hydroxylase/17,20 lyase, StAR deficiencies.