Sex Characteristics/Development

Question 1

What is X Chromosome inactivation? During what week of development does it typically occur? What gene is responsible? What is the mechanism?

Answer 1

Creation of a Barr body; week 1 of embryogenesis; XIST gene is responsible; Expression ON THE INACTIVATED GENE, methylation of Cytosine shuts down promoters

Question 2

What are 3 types of X inactivation? What are the distinguishing features?

Answer 2

1. Random (50/50 mix of expression) 2. non-random (undamaged X favored 3. Skewed (not 50/50, damaged may be expressed leading to phenotypic expression of X-linked recessive traits in female ie fragile X)

Question 3

47,XXX

Answer 3

– May have tall stature
– Increased risk of
• Learning disabilities
• Delayed speech
• Delayed motor milestones • Seizures
• Kidney Abnormalities
– Occurs in 1/1000 newborn girls

Question 4

Gonad Determination is ________

Answer 4

Chromosomal.

Question 5

Secondary Sex characteristic development is ________.

Answer 5

Hormonal. Gonads determine secondary sex characteristics.

Question 6

What notable event takes place during the 7th week of conception regarding sexual development?

Answer 6

Differentiation of genital ridge into male/female structures. In male embryo, differentiation of genital ridge begins.
Sertoli cells - eventually produce sperm
Leydig cells – interstitial cells

Question 7

What notable event takes place during the 8th week of conception?

Answer 7

– Leydig cells begin producing testosterone
– Sertoli cells begin producing Anti-Mullerian Hormone (AMH)
– Primitive sex cords differentiate into
• Testis cords & rete testis, eventually to become seminipherous tubules during puberty

Question 8

During the 7th/8th week of development, in the absence of SRY and the presence of XX chromosomes, what happens?

Answer 8

Primitive sex cords dissociate, destined to become the follicular cells of the ovary. Follicular cells eventually surround an oogonium which together are the primary ovarian follicle.

Question 9

The mesonephric duct, aka ________, eventually results in _____ structures under the influence of_____.

Answer 9

Wolffian; male (Epidymis, Seminal vesicles, Vas deferens); testosterone

Question 10

The paramesonephric, aka ______ duct, eventually results in ______ structures under the influence of _____.

Answer 10

Mullerian; female (Uterus Cervix Broad ligament Fallopian Tubes Upper 1/3 of the vagina); estrogen

Question 11

What are three genes involved in development of male reproductive structures? What does each do?

Answer 11

1. SRY and SOX 9 (Both transcription factors responsible for production of Anti-Mullerian Horomone [aka Mullerian Inhibitory Substance - MIS] Causes regression of the paramesonephric duct.
2. FGF9 (Chemotactic factor causes tubules from mesonephric duct to penetrate the gonadal ridge. Essential for differentiation of the testis)
3. SF1/NR5A1
   (Stimulates differentiation of the Sertoli & Leydic cells)

Question 12

What are three genes involved in development of female reproductive structures? What does each do?

Answer 12

1. WNT4 protein (Extracellular signaling factor responsible for differentiation of the ovary. Inhibited by SOX9)
2. DHH gene (A nuclear hormone receptor Up-regulated by WNT4, Downregulates SOX9)
3. RSPO1 gene (Coactivator of the WNT pathway)

Question 13

External genitalia develop from what original structure?

Answer 13

Urogenital sinus, (and the genital tubercle/genital swellings starting in week 3)

Question 14

Androgen exposure (in this case______) from the testis results in the formation of the following (3):

Answer 14

Dihydrotestosterone; penis, scrotum, location of urethra at top of penis

Question 15

Estrogen exposure resulting from maternal and placental sources results in the formation of the following (3):

Answer 15

Clitoris, Labia majora and minora, Lower 2/3 of the vagina

Question 16

Clinical Approach to Disorders of Sexual Differentiation (1st day of life)

Answer 16

– Obtain FISH studies for Sex Chromosomes and a Karyotype (or Chromosomal Microarray)
– Order hormone studies
• LH, FSH, Testosterone, Dihydrotestosterone, +/- AMH
– Consider ultrasound study • Evaluate for gonads & uterus
– Surgical consult with Urology

Question 17

Androgen Insensitivity Syndrome (AIS)

Answer 17

– 46, XY
– X-linked gene, AR
– Mutation causes abnormality of the androgen receptor
• Even though the body makes androgens (testosterone), it doesn’t necessarily recognize or respond to it
• Phenotypes range from mild under-virilization (Partial AIS) to full sex reversal (Complete AIS)
– Previously called “Testicular feminization”

Question 18

5-Alpha Reductase Deficiency

Answer 18

– 46, XY
– X-linked gene, AR
– Mutation causes decreased ability of the body
to convert testosterone to dihydrotestosterone
– Phenotype shows undervirilized male with increased virilization at the time of puberty

Question 19

Deletion or absence of SRY gene results in ______.

Answer 19

full 46, XY sex reversal and a phenotypically normal female

Question 20

Ectopic presence of the SRY gene in a 46, XX individual results in ______.

Answer 20

a phenotypically normal male

Question 21

Mutations in the SRY gene in a 46, XY individual results in ______.

Answer 21

decreased or absent production of Anti Mullerian hormone & under virilization of a male

Question 22

Denys-Drash & Frasier Syndrome both involve what?

Answer 22

WT1 mutation (transcription factor for SRY gene). Both involve kidney sclerosis and high potential for gonadal tumors (often surgically removed).

Question 23

Congenital Adrenal Hyperplasia

Answer 23

– Ambiguous genitalia in 46, XX
– 21-hydroxylase deficiency
– Complicated by salt wasting in the first few weeks of life and with times of metabolic stress
• Decreased sodium and chloride • Increased potassium