Editing Disorders of Sexual Differentiation (section)

===== Complete (Severe) Androgen Insensitivity Syndrome (CAIS) =====
* Incidence of 1 in 20,000 to 1 in 60,000 males
* '''X-linked trait'''
** '''The androgen receptor has been mapped to the X chromosome'''
** Males have only one copy of this gene
** Point mutations of the gene account for > 90% of cases of androgen insensitivity
* '''Characterized by 46,XY karyotype, bilateral testes, female-appearing external genitalia, and absence of müllerian-derived structures,''' consistent with functioning Sertoli cells
** Patients have a normal female phenotype with the exception of diminished axillary and pubic hair.
*** Breast development and body habitus are feminine in character
**** '''At puberty, gonadotropin levels rise, leading to increased levels of plasma estradiol, which results in feminization, including breast development.'''
*** '''≈80% will have "normal" appearing, although the vagina is short and blind ending.'''
** Wolffian-derived structures may be present
*** Screening of the paratesticular area revealed well-developed epididymis and/or vasa deferentia in 42% of patients
** The testes may be found in the labia, inguinal canal, or abdomen
* '''Rarely diagnosed in the neonatal period; patients typically present by one of 5 different means:'''
*# Fetal karyotype (46 XY) incongruent with newborn infant's phenotype (5% of patients)
*# Relative or family member with CAIS, with patient diagnosed due to recommendation for genetic screening (15% of patients)
*# Ambiguous genitalia at birth, i.e., female phenotype with palpable gonads or mild to moderate clitorimegaly (20% of patients)
*# '''Primary amenorrhea (30% of patients)'''
*# '''Testicle found within a inguinal hernia at the time of surgical repair (30% of patients)'''
*#* Vaginoscopy to confirm the presence of a cervix or endoscopy through a hernia sac to identify an intra-abdominal testis at the time of inguinal herniorrhaphy in female patients is a prudent maneuver.
* '''Diagnosis and Evaluation'''
** '''History and Physical Exam'''
*** '''May readily be made in the postpubertal patient on the basis of clinical and hormonal findings of amenorrhea, absence of pubic hair, or inguinal hernias containing testes'''
*** '''Vaginal examination confirms a blind-ending vagina without a cervix'''
** '''Labs'''
*** '''Karyotype: 46,XY'''
*** '''Endocrine evaluation'''
**** '''Neonatal period: normal male levels of testosterone, DHT, and gonadotropins'''
**** '''Puberty:'''
***** '''Testosterone production and secretion by the Leydig cells is normal'''
***** '''LH is increased because of the apparent lack of testosterone by the target organs including the pituitary gland that not recognize the testosterone due to faulty receptors.'''
***** '''FSH is normal since it is controlled by inhibin'''
**** '''In the prepubertal child, diagnosis is more difficult and requires an hCG stimulation test.'''
***** [Unlike 17β-Hydroxysteroid Oxidoreductase Deficiency, hCG stimulation test in androgen insensitivity would not result in an increased testosterone-to-androstenedione ratio]
*** PCR can be used characterize the androgen receptor gene
** '''Imaging'''
*** '''Pelvic US confirms the absence of müllerian-derived structures'''
* '''Management'''
** '''Relates primarily to the optimal timing of gonadectomy'''
*** '''Patients with CAIS will have a substantial increased risk of developing a testicular seminoma'''
**** If the testis is left in situ, ≈20% of the patients will have developed a testicular malignancy by the age of 30.
**** '''Removal of the testicles are, therefore, strongly recommended either prior to or immediately following pubescence'''
***** '''Because the testes produce estradiol, which results in the appropriate changes for the female phenotype, it is considered by many preferable to leave the testes in situ until puberty is complete. In general, delayed gonadectomy after puberty is believed to be safe'''
***** '''Gonadoblastoma is a tumor that is associated with disorders of sex development. Specifically, it is found in infants noted to have partial or pure gonadal dysgenesis (46 XY or 46 XY/XO genotypes) and is not associated with complete androgen insensitivity syndrome'''
*** '''After orchiectomy, cyclic estrogen-progestin therapy is begun.'''
** '''All studies CAIS have been in patients with an unequivocal female gender identity''', consistent with androgen resistance of brain tissue as well.