Disorders of sex development Flashcards
Definition
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).
Most common causes
●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
CAUSES OF XX DSD
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
Causes of atypical genitalia in XY individuals
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)
Congenital adrenal hyperplasia etiology
AR defects in the enzymes that are responsible for cortisol, aldosterone, androgen synthesis
Subtypes of CAH
21beta - hydroxylase = 95%
11beta - hydroxylase = 5%
17alpha - hydroxylase = rare
Hyperplasia due to?
Low levels of cortisol due to the enzyme defect, lack of negative feedback to the pituitary -> increased ACTH -> adrenal hyperplasia
21b - hydroxylase deficiency XX genotype
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
21b - hydroxylase deficiency XY genotype
Hypotension
Normal male external genitalia at birth
Precocious puberty due to excess androgen
11β-hydroxylase XX
Hypertension
Female pseudohermaphroditism: clitoromegaly and/or male external genitalia along with a uterus and ovaries
Precocious puberty
Virilization, irregular menstrual cycles, infertility
11β-hydroxylase XY
Hypertension
Normal male external genitalia at birth
Precocious puberty
General clinical features CAH
Hypoglycemia
Adrenal crisis > vomiting and diarrhea > dehydration
Failure to thrive
Hyperpigmentation
Diagnostics CAH
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
Tx general CAH
General: replace deficient hormones and reduce excess androgen production
Glucocorticoid replacement therapy indicated in all forms of CAH
Specific Tx 21β-hydroxylase deficiency
Lifelong aldosterone substitution Sodium chloride (salt) supplements, especially during infancy and childhood
Specific Tx 11β-hydroxylase deficiency
Spironolactone to block mineralocorticoid receptors
Reduced dietary sodium intake
Salt-wasting CAH
- Fluid resuscitation with intravenous normal saline
- Intravenous dextrose in patients with significant hypoglycemia
- Immediate administration of glucocorticoid replacement therapy
- Androgen insensitivity syndrome cause
X-linked recessive mutation of the gene encoding the androgen receptor
Karotype 46 XY
Defects in androgen receptor
- Androgen insensitivity syndrome types
Complete or partial androgen insensitivity
Diagnosis complete Androgen insensitivity syndrome
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
Clinical features CAIS
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
Partial androgen insensitivity syndrome (PAIS)
characterized by
- a variable phenotype from phenotypic women with mild virilization to phenotypic men with undervirilization and gynecomastia or infertility
