Embryology and CAH

Question 1

Gonadal development

Answer 1

Undifferentiated gonads first appears at about 4-5 wks as paired genital ridges

Genital ridges form in the posterior abdominal wall just medial to the developing mesonephros

Formed from proliferation of the epithelium and condensation of underlying mesenchyme

Question 2

WT-1

Answer 2

Wilms tumor related gene

• a TF in genital ridge
• Expressed in the developing genital ridge, kidney, and gonads

-deletions/mutations associated with gonadal dysgenesis and predilection for Wilms tumor and nephropathy

Question 3

NR5A1

Answer 3

aka steroidogenic factor (SF-1)
Regulates transcription of genes involved in gonadal and adrenal development, steroidogenesis, and reproduction

SF-1 deletions can cause gonadal dysgenesis, adrenal failure, and persistent mullerian structures

Question 4

When do germ cells migrate from yolk sac and invade genital ridge?

Answer 4

6 weeks

Question 5

What happens if germ cells don’t migrate? If they do what is next?

Answer 5

If not: gonads don’t develop

If do:
Shortly before and during arrival of primordial germ cells, the epithelium of the genital ridge proliferates, and epithelial cells penetrate the underlying mesenchyme, forming the primitive sex cords
Indifferent gonad has an inner medulla and outer cortex

Question 6

SRY

Answer 6

6 wks: expression of SRY leads to gonads differentiating into testes
Primitive sex cords continue to proliferate and penetrate deep into the medulla to form the testis or medullary cords
Migration of mesonephric cells into developing testis
Differentiation of sertoli cells (from surface epithelium) and differentiation of leydig cells
Leydig cells make testosterone

Question 7

SOX-9

Answer 7

-TF imp for testicular differentiation
-Target of SRY
Essential for normal testis formation
With SF-1, elevates AMH concentrations
Deletions or mutations -camptomelic dysplasia
Severe skeletal dysplasia
Gonadal dysgenesis in approximately 75% of patients

Know: WT1, SF1, SRY, SOX-9

Question 8

Testis formation/devel

Answer 8

At hilum , the testis cords form rete testis
A dense layer of fibrous connective tissue, the tunica albuginea, separates the testis cords from the surface epithelium
Testis cords are now composed of PGC’s and Sertoli cells
Leydig cells lie between the testis cords and begin production of testosterone by 8th week

Question 9

Mesonephric duct becomes

Answer 9

ductus deferens

Question 10

Ovarian devel

Answer 10

• need two X and no Y
• Genes: DAX1, WNT4, RSPO1, FOXL2
• cortex develops into ovaries and medulla fades away (degeneration of medullary sex cords)

Question 11

Internal ducts

Answer 11

• both mesonephric (wolffian) and paramesonephric (Mullerian) ducts develop in both sexes
• differentiation of ducts begins at 8 wks (same time males start making testosterone)

Male: paramesonephric ducts go away

Question 12

What do the wolffian ducts develop into?

Answer 12

epididymis
vas deferens (ductus deferens)
seminal vesicles

Question 13

What is necessary for male internal ducts to develop?

Answer 13

1. High local concentrations of testosterone
   Produced by Leydig cells
2. Antimullerian hormone (AMH)
   Produced by the Sertoli cells
   Induces müllerian duct regression
   Must be expressed before the end of the 8th week in the human fetus

Question 14

What about female internal ducts?

Answer 14

-absence of local testosterone and AMH
-Paramesonephric/Mullerian ducts:
Fallopian tubes
Midline uterus
Upper portion of vagina

Wollfian ducts regress

Question 15

Rokitansky syndrome

Answer 15

absent or underdeveloped Mullerian structures in 46 XX female
(breast and hair development but primary amenorrhea)

Question 16

Persistent Mullerian ducts in 46 XY

Answer 16

• defect in AMH synthesis

- defect in AMH receptor

Question 17

External Genitalia

Answer 17

Devel from:
genital tubercle: glans penis or clitoris

urethral folds: penile urethra or labia minora

labial-scrotal (genital) swellings: scrotum or labia majora

Question 18

Male hormones for external genitalia development

Answer 18

Dependent upon testosterone and dihydrotestosterone (DHT)
Testosterone converted to DHT by 5 alpha-reductase
DHT has higher receptor affinity than testosterone
Penile growth and formation of penile urethra is particularly dependent on DHT

(undervirilized?: can see hypospadias)

In 1st trimester, placental HCG stimulates leydig cells to make testosterone (HCG is like LH)

After 1st trimester, hypothalamic-pituitary-testicular axis required for continued testosterone production

Male external genitalia complete by 13 weeks

(If female exposed to testosterone before 13 weeks: some virilization will occur; after 13 weeks, would cause enlargement of clitoris)

Question 19

Psychosocial development

Answer 19

Three components:

1. Gender identity
2. Gender role
3. Sexual orientation

Role of fetal exposure to androgens:
46XX CAH: male gender role behavior in childhood
46XY w/cloacal extrophy raised as girls have a high rate of gender dysphoria

Question 20

Disorder of sex development

Answer 20

Congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical

46 XX DSD (virilized)
46 XY DSD (undervirilized)

Generally ovaries don’t descend (feel testis in scrotum)

Question 21

Eval of DSD

Answer 21

Palpable gonads?
Position of urethral meatus
Degree of fusion
 Stretched penile length
Term over 2.5 cm
Clitoral length less than 1.0 cm and diameter less than 0.6 cm

Prader classification

Clinical eval:
FISH for Y (SRY)
send karyotype
US to check for uterus (probably wasn't AMH if there is a uterus, so palpable gonad is likely ovary)
Laparoscopy

Question 22

46 XX DSD: diagnoses

Answer 22

Congenital Adrenal Hyperplasia - 95% of the time

46,XX sex reversal (SRY translocation)

Ovotesticular DSD

Gestational hyperandrogenism

Question 23

46, XY DSD

Answer 23

Abnormal testicular development:

-Pure or partial gonadal dysgenesis:
SRY mutations
Underexpression of SOX9 associated with campomelic dysplasia
SF1 mutations
WT1 mutations
Duplication of DAX1
Duplication of Wnt-4
Underexpression of DMRT1 and DMRT2 (9p24.3)
ATR-X syndrome
Underexpression of DHH

• Mixed gonadal dysgenesis (45X/46,XY)
• Testicular regression (thought to be vascular accident late in gestation)
• Leydig cell dysfunction

Question 24

5 alpha-reductase deficiency

Answer 24

Autosomal recessive disorder
Results in low dihydrotestosterone (DHT) levels

Males are undervirilized
Testes usually in inguinal canal or labial-scrotal folds
Wollfian ducts differentiated
At puberty, spontaneous virilization occurs
High rate of male gender identity

Question 25

46 XY DSD: defects in androgen action

Answer 25

Complete androgen insensitivity syndrome Partial androgen insensitivity syndrome Androgen Insensitivity Syndrome 1:20,000 to 1:64,000 male births Mutation in Androgen Receptor gene Complete (CAIS) - normal female external genitalia with short vagina and absence of Mullerian and Wollfian structures *chart

Question 26

CAIS

Answer 26

Complete AIS: Gonads intraabdominal or in inguinal canal Bilateral inguinal hernias common At time of puberty, spontaneous breast development due to testosterone conversion to estrogen Little or no pubic/axillary hair Female gender identity

Question 27

Management

Answer 27

Avoid gender assignment before expert evaluation Conduct evaluation and management in a center with experienced interdisciplinary team Give a gender assignment to all individuals Openly communicate with patients and families, and respect their concerns and address them in strict confidence

Question 28

Adrenal Cortex

Answer 28

from mesoderm Zona Glomerulosa – Mineralocorticoids Zona Fasciculata – Glucocorticoids Zona Reticularis - Androgens

Question 29

Congenital adrenal hyperplasia: most common defect

Answer 29

21- hydroxylase (95%) -Most prominent feature: virilization In female infant – virilization of external genitalia In male infant – no genital abnormalities

Question 30

Clinical features of 21 hydroxylase deficiency

Answer 30

``` Hyperpigmentation (elevated MSH, and ACTH can also promote pigmentation) Hyponatremia/hyperkalemia due to aldosterone deficiency Mild forms (nonclassical) may present later in life with early pubic hair, axillary hair, penile/clitoral enlargement ```

Question 31

**Dx of 21 hydroxylase deficiency

Answer 31

Autosomal recessive Classical 1:14,000 Nonclassical 1:100 21-OHase gene on short arm of chromosome 6 Diagnosis suspected in virilized XX infant or in XY infant who presents with hyponatremia and hyperkalemia Diagnosis confirmed by measuring 17-OH progesterone 17-OH progesterone now measured on newborn screen False positive results in stressed, premature, and low birthweight infants

Question 32

**Tx of 21 hydroxylase def

Answer 32

Surgery in females Replace deficient hormones and suppress ACTH overproduction Glucocorticoid deficiency – hydrocortisone (increased doses for illness/stress) Mineralocorticoid deficiency- florinef (infants also need salt supplements Acute Adrenal Insufficiency – IM or IV Solu-Cortef

Question 33

Congenital Adrenal hyperplasia: 11 beta hydroxylase deficiency for the rest: know which ones are salt wasting

Answer 33

1/100,000 Virilization similar to 21-OHase deficiency No salt wasting as 11-deoxycorticosterone has mineralocorticoid activity Hypertension is a frequent finding

Question 34

CAH: StAR protein

Answer 34

less than 1% Congenital Lipoid Hyperplasia “Lipoid” refers to accumulation of cholesterol esters in the adrenocortical tissue StAR (Steroidogenic Acute Regulatory) protein is involved in transfer of cholesterol from outer to inner mitochondrial membrane Females have normal genitalia Males have female external genitalia Salt –wasting Fatal if not detected early in infancy

Question 35

CAH: 3 beta hydroxysteroid dehydrogenase

Answer 35

-in boys: don't make enough androgens Virilization in girls Undervirilization in boys Salt-wasting

Question 36

CAH: 17 alpha hydroxylase/17, 20 lyase

Answer 36

Hypertension secondary to increased 11-deoxycorticosterone Hypokalemia Females born with normal genitalia and present at puberty with failure to develop secondary sex characteristics Males born undervirilized