Disorders of sex development

Question 1

Definition

Answer 1

Group of congenital conditions that affect the development of the chromosome, gonadal or phenotypic sex.
Infants born with genitals that do not appear typically male or female or that have an appearance discordant with the chromosomal sex are classified as having a disorder of sex development (DSD).

Question 2

Most common causes

Answer 2

●Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in an XX individual

●Sex chromosome DSD (X/XY mosaicism)

●Androgen insensitivity syndrome in an XY individual

Question 3

CAUSES OF XX DSD

Answer 3

Caused by excessive androgen action, which can be due to

• overproduction of androgens by the adrenal cortex,
• excessive production of testosterone by the gonads,
• an ectopic or exogenous source of androgens

Question 4

Causes of atypical genitalia in XY individuals

Answer 4

Occur because of insufficient dihydrotestosterone action. This can be caused by

• global defect in testicular function (gonadal dysgenesis), - a specific defect in dihydrotestosterone production,
• an inability to respond to dihydrotestosterone and other androgens (androgen insensitivity)

Question 5

Congenital adrenal hyperplasia etiology

Answer 5

AR defects in the enzymes that are responsible for cortisol, aldosterone, androgen synthesis

Question 6

Subtypes of CAH

Answer 6

21beta - hydroxylase = 95%
11beta - hydroxylase = 5%
17alpha - hydroxylase = rare

Question 7

Hyperplasia due to?

Answer 7

Low levels of cortisol due to the enzyme defect, lack of negative feedback to the pituitary -> increased ACTH -> adrenal hyperplasia

Question 8

21b - hydroxylase deficiency XX genotype

Answer 8

Hypotension (no cortisol)
Female pseudohermaphrodism: clitoromegaly and or male external genitalia + uterus and ovaries
Precocious puberty - excess androgen are aromatized to estrogen by aromatase in ovaries
Virilization, irregular menstrual cycles, infertility

Question 9

21b - hydroxylase deficiency XY genotype

Answer 9

Hypotension
Normal male external genitalia at birth
Precocious puberty due to excess androgen

Question 10

11β-hydroxylase XX

Answer 10

Hypertension
Female pseudohermaphroditism: clitoromegaly and/or male external genitalia along with a uterus and ovaries
Precocious puberty
Virilization, irregular menstrual cycles, infertility

Question 11

11β-hydroxylase XY

Answer 11

Hypertension
Normal male external genitalia at birth
Precocious puberty

Question 12

General clinical features CAH

Answer 12

Hypoglycemia
Adrenal crisis > vomiting and diarrhea > dehydration
Failure to thrive
Hyperpigmentation

Question 13

Diagnostics CAH

Answer 13

Increased specific steroid precursor in blood and/or urine:
- conducted by measuring 17-hydroxyprogesterone
Hypocortisolism is seen in all forms
21alpha - low sodium, potassium
Metabolic acidocis
11b - high sodium, low potassium
Metabolic alkalosis

Question 14

Tx general CAH

Answer 14

General: replace deficient hormones and reduce excess androgen production
Glucocorticoid replacement therapy indicated in all forms of CAH

Question 15

Specific Tx 21β-hydroxylase deficiency

Answer 15

Lifelong aldosterone substitution
Sodium chloride (salt) supplements, especially during infancy and childhood

Question 16

Specific Tx 11β-hydroxylase deficiency

Answer 16

Spironolactone to block mineralocorticoid receptors

Reduced dietary sodium intake

Question 17

Salt-wasting CAH

Answer 17

• Fluid resuscitation with intravenous normal saline
• Intravenous dextrose in patients with significant hypoglycemia
• Immediate administration of glucocorticoid replacement therapy

Question 18

2. Androgen insensitivity syndrome cause

Answer 18

X-linked recessive mutation of the gene encoding the androgen receptor
Karotype 46 XY
Defects in androgen receptor

Question 19

2. Androgen insensitivity syndrome types

Answer 19

Complete or partial androgen insensitivity

Question 20

Diagnosis complete Androgen insensitivity syndrome

Answer 20

The diagnosis, which is typically made in an adolescent or young adult woman, is based upon a constellation of clinical and biochemical findings:

Female phenotype with normal breast development
Primary amenorrhea
Little or no axillary or pubic hair
Absent uterus, but testes present
Before puberty: increased testosterone
After puberty: increased LH, estrogen, normal/increased testosterone
Ø virilization
testes may be located in the abdomen or inguinal region
no androgen sensitive organs = Ø negative feedback

Question 21

Clinical features CAIS

Answer 21

Characterized by an external female phenotype in a 46,XY individual with

• absent or sparse genital hair,
• absent uterus,
• serum testosterone concentrations that are higher than or within the usual male range
• ability to synthesize testosterone

Question 22

Partial androgen insensitivity syndrome (PAIS)

Answer 22

characterized by
- a variable phenotype from phenotypic women with mild virilization to phenotypic men with undervirilization and gynecomastia or infertility