Editing Disorders of Sexual Differentiation (section)

==== Congenital Adrenal Hyperplasia ====
* Pathogenesis
** Classic example of an inborn error of metabolism—in this case, an error involving cortisol synthesis
** '''A defect in any of the enzymes involved in the steroidogenesis pathway may result in CAH'''
**# '''21-hydroxylase deficiency'''
**#* '''Autosomal recessive inheritance'''
**#* '''Most common (95%) cause of CAH'''
**# '''11β-hydroxylase deficiency'''
**#* '''Second most common (5%) cause of CA'''
**# '''3β-hydroxysteroid dehydrogenase deficiency'''
**#* '''Least common enzyme deficiency responsible for a virilizing form of CAH'''
*** '''Deficiencies in 21-hydroxylase or 11β-hydroxylase results in impaired formation of cortisol, causing a compensatory increase in the secretion of ACTH. This increased ACTH enhances formation of adrenal steroids proximal to the enzymatic defect and a secondary increase in the formation of testosterone, the active androgen in CAH'''.
[[File:Steroidogenesis.png|center|thumb|512x512px|Steroidogenesis. Source: Wikipedia]]

* '''Categorized clinically (3):'''
*# '''Classic salt wasters: virilization and aldosterone deficiency'''
*# '''Simple virilizers: virilization without aldosterone deficiency'''
*# '''Non-classic patients: neither virilization nor aldosterone deficiency'''
** Wide clinical spectrum likely due to different degrees of enzymatic dysfunction conferred by specific, identifiable genetic defects.
** The severity of the virilization is usually greater in infants who experience salt wasting

* '''Classic salt wasters'''
** '''In the female with the classic salt-wasting and simple virilizing forms of the disorder, a masculinized female results'''
*** '''Because impaired steroidogenesis begins early in life—at the time of formation of the external genitalia (beginning at 10 weeks’ gestation)— there is virtually always evidence of some degree of masculinization at birth. This manifests as enlargement of the clitoris and varying degrees of labial fusion'''
** '''In both males and females, symptoms related to salt-deficiency and hypocortisolism begin within the first few weeks after birth, with failure to regain birth weight, progressive weight loss, and dehydration.'''
*** '''In severely affected infants, adrenal crises occur within the first 10 to 21 days of life.'''  
*** Vomiting is prominent and can be so extreme that a mistaken diagnosis of pyloric stenosis is made, particularly in the male.

* '''Simple virilizers'''
** '''In males with the simple-virilizer form, the main clinical manifestations are those of isosexual precocity'''
*** '''The infant appears normal at birth, but signs of sexual and somatic precocity appear within the first 2-3 years of life.'''
**** '''Enlargement of the penis, scrotum, and prostate occur, accompanied by the appearance of pubic hair, acne, and deepening of the voice'''
**** '''Musculature is well developed''' (prompting the descriptive term “little Hercules”), and '''bone age is more advanced''' than appropriate for the chronologic age.
**** '''Testes remain normal in size'''
*** '''Two major long-term implications are short stature as well as infertility'''
**** '''Infertility is often related to the finding of testicular adrenal rest nodules'''
***** Adrenal rest nodules are most reliably diagnosed with scrotal ultrasonography
***** Treatment may involve intensifying glucocorticoid treatment and testis-sparing excision

* '''21-hydroxylase deficiency'''
** '''Patients with 21-hydroxylase deficiency usually have either the classic salt wasting (75%) or simple virilization (25%) form'''
*** '''Mutations leading to gene conversion of the active CYP21A gene into the inactive gene occur in 65-90% of cases of the classic disorder (salt wasting and simple virilizing) and all cases of non-classic 21-hydroxylase deficiency'''
*** '''Non-classic 21-hydroxylase deficiency'''
**** '''Represents an attenuated, late-onset form that is variable in its clinical severity because of partial deficiency of 21-hydroxylase and timing of onset'''
**** Incidence:1 in 100
***** '''Most common autosomal recessive disorder in humans'''
**** '''Patients do not have cortisol deficiency but do have hyperandrogenism''' [less severe than virilization?]
***** The presenting symptoms in females are commonly hirsutism and oligomenorrhea, male pattern baldness, and polycystic ovaries.
** '''Diagnosis and Evaluation'''
*** '''History and Physical Exam'''
**** Radioimmunoassay for 17-hydroxyprogesterone
***** Has replaced the more cumbersome 24-hour urine collection of metabolites (e.g., pregnanetriol).
**** '''In classic salt-wasting 21-hydroxylase deficiency:'''
***** '''Plasma levels of progesterone and 17-hydroxyprogesterone are markedly elevated.'''
***** '''Urinary levels of 17-ketosteroids and pregnanetriol are elevated.'''
*** '''Imaging: pelvic US'''
**** '''A pelvic US study demonstrating the presence of müllerian tissues (e.g. uterus) is confirmatory'''
**** Some investigators have suggested that the finding of abnormally enlarged or “cerebriform”-appearing adrenal glands on neonatal ultrasonography, available before biochemical results, may represent the earliest diagnostic tool for CAH
**** '''Increased incidence of upper tract abnormalities (hydronephrosis, duplication) in CAH'''

* '''11β-hydroxylase deficiency'''
** '''Hypertension is a common finding'''
*** '''Believed to be secondary to increased serum levels of deoxycorticosterone (DOC), which are not elevated in 21-hydroxylase deficiency'''
** '''Marked virilization occurs in the severe form of the defect and may be as severe as in those patients with a 21-hydroxylase deficiency.'''
*** In the late-onset form, mild virilization occurs in prepubertal and postpubertal patients.
** '''Diagnosis and Evaluation'''
*** '''Labs: increased plasma levels of 11-deoxycortisol and 11-DOC.'''
**** Urinary levels of 17-ketosteroids and 17-hydroxycorticoids are increased.
*** Pelvic ultrasound evaluation in females confirming the presence of müllerian tissue would be supportive
* '''3β-hydroxysteroid dehydrogenase deficiency'''
** '''Affects the early steps in steroid biosynthesis in both adrenals and gonads'''
** '''Various degrees of incomplete masculinization, resulting from a block in testosterone biosynthesis, and salt-wasting aldosterone insufficiency resulting from impaired synthesis of aldosterone and cortisol.'''
*** '''The severe form leads to impaired synthesis of aldosterone, cortisol, and sex steroids.'''
*** Males with this deficiency usually exhibit incomplete virilization of the external genitalia, with a small phallus, hypospadias with labioscrotal fusion, a urogenital sinus, and a blind-ending vaginal pouch. Testes are often scrotal, and wolffian duct-derived structures develop normally.
*** As with other defects in testosterone biosynthesis, in which normal Sertoli cell function is preserved, müllerian-derived structures structures are absent
** '''Diagnosis and Evaluation'''
*** Should be considered in 46,XY males with ambiguous genitalia and signs of adrenal insufficiency
*** '''Labs: increased serum levels of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA)'''
*** Pelvic ultrasound evaluation in females confirming the presence of müllerian tissue would be supportive

* '''Management'''
** '''Glucocorticoids'''
** “Prophylactic” adrenalectomy
*** Considered for selected patients is based on the premise that in certain patients it is more difficult to maintain adrenal suppression than to prevent adrenal crises. Clinically, these patients are the salt wasters and extremely virilized females.
*** For the 25% of CAH patients who completely lack 21-hydroxylase enzyme activity and therefore produce neither cortisol nor aldosterone, adrenalectomy may be a practical approach
* '''Prognosis'''
** '''Long-term fertility in males and feminization, menstruation, and fertility in females can be anticipated in the well-treated patient.'''
** '''Males with CAH must be followed for testicular adrenal rest tumors as a potential cause of infertility'''. This is ideally performed with annual screening testicular ultrasonography
*** In patients with CAH, adrenal rests along the spermatic cord may become quite large

* '''Diagnosing and treating the CAH prenatally'''
** '''Diagnosis is made during the first trimester''', usually by HLA genotyping or by DNA analysis of genes by chorionic villus sampling at 9-11 weeks’ gestation
** '''Management'''
*** '''Treatment of the mother with dexamethasone, which crosses the placenta, suppresses fetal secretion of ACTH,''' thereby preventing virilization of the genitalia.
**** '''Once pregnancy is confirmed, treatment should be initiated before 9 weeks after the last menstrual period.'''
***** '''However, a diagnosis of CAH cannot be confirmed before therapy is initiated because the diagnosis is usually made''' '''at 9-11 weeks’ gestation.''' Therefore, if treatment is initiated for all at-risk fetuses, 7/8 may be treated unnecessarily before confirmatory diagnosis.