Contents
Congenital adrenal disease causing defective steroidogenesis (glucocorticoids, mineralocorticoids, or sex steroids).
- Autosomal recessive inheritance
- M/C cause of adrenal insufficiency in the pediatric age group
- M/C inborn error in adrenal function
History:
In 1865, Luigi de Crecchio, a Neapolitan anatomist, reported the earliest documented description of a patient presumed to have 21-hydroxylase deficiency. At autopsy, the cadaver was described as having labioscrotal fusion, a 10 cm curved phallus with hypospadias, bilateral undescended testes, a vagina, a uterus, fallopian tubes, ovaries, and markedly enlarged adrenal glands. This individual had ambiguous genitalia at birth, reportedly presented as a male throughout his adult life, and presumably died of adrenal insufficiency in his 40s during an episode of vomiting, diarrhea, and prostration. Just over 100 years later in 1957, the nonclassic or mild form of 21-hydroxylase deficiency was described by Jacques Decourt, Max-Fernand Jayle, and Ettiene Baulieu.
Physiology
Adrenal gland endocrinology:
Three classes of steroid hormone are produced by the adrenal cortex after uptake of precursor cholesterol from the plasma: mineralocorticoids, glucocorticoids and sex steroids
- Zona glomerulosa | Mineralocorticoids (aldosterone and deoxycorticosterone): Aldosterone secretion is principally under the control of the renin–angiotensin–aldosterone system and its action leads to enhanced uptake of sodium in the distal renal tubule following binding to the mineralocorticoid receptor.
- Zona fasciculata | Glucocorticoids (cortisol and corticosterone): Secreted in response to stimulation by adrenocorticotrophic hormone (ACTH) and have wide-ranging effects mediated by the glucocorticoid receptors.
- Zona reticularis | Androgens (sex steroids)
Steroidogenic pathway:
The glucocorticoid (cortisol), mineralocorticoid (aldosterone), and adrenal androgen synthetic pathways are the focus of the pathophysiology of CAH. ACTH binds to its receptor, the MC2R, which is a G-protein coupled receptor that increases adenylyl cyclase activity and cytoplasmic cAMP concentration (see Fig. 1). Increased cAMP then leads to an activation of StAR protein and an increase in cholesterol transport into the mitochondria.
Pathophysiology
Congenital adrenal hyperplasia (CAH:
Inadequate cortisol production in the fetus provides subnormal negative feedback inhibition of the fetal hypothalamus and pituitary. This leads to an increase in fetal plasma ACTH in an attempt to normalize fetal cortisol. The increase in fetal plasma ACTH increases StAR-mediated cholesterol transport into the mitochondria to acutely increase steroidogenesis in the fetal adrenal gland. In the long term, the increased ACTH leads to hyperplasia of the fetal adrenal cortex with a dramatic increase in size of the fetal adrenal gland. A consequence of this increased activity in the early steroidogenic pathway is an increase in the production of precursors for adrenal androgens (e.g., 17-α-OH-progesterone) upstream from the enzyme deficiency. This will lead to steroid precursor “spill-over” into the androgen pathway resulting in enormous increases in, for example, DHEA. Whereas DHEA is a relatively weak androgen under usual circumstances, the enormous increase in DHEA in an XX fetus can lead to virilization of the highly steroid sensitive genitalia during fetal development. As a result, an XX-fetus can be born with ambiguous genitalia
Steroid 21-hydroxylase deficiency (M/C, 90% cases):
Function of 21-hydroxylating cytochrome P450 is deficient, creating a block in P450 cortisol production pathway. This leads to an accumulation of 17-hydroxyprogesterone (17-OHP), a precursor adjacent of the 21-hydroxylation step. Excess 17-OHP is then shunted into the intact androgen pathway, where the 17,20-lyase enzyme converts the 17-OHP to Δ4-androstenedione, the major adrenal androgen.
- Classical form: Complete 23 hydroxylase deficiency
- Salt wasting type: Severe form in which both coritsol and aldosterone deficient with excess androgens
- Simple virilizing type: Impaired synthesis of cortisol and adequate amounts of aldosterone. Clinical features manifest solely due to excess androgens.
- Non-classical form: Characterized by partial 21-hydrocylase deficiency in which normal levels of cortisol and aldosterone are present with excess androgen production
Other enzyme deficiencies:
- 11β-hydroxylase deficiency (#2 M/C): M/C enzyme deficiency leading to childhood hypertension
- 17α-hydroxylase deficiency
- 3β-HSD (hydroxysteroid dehydrogenase) deficiency
Clinical features
Virilization of female genitalia:
Adrenocortical function begins at the 7th week of gestation; thus, a female fetus with classical CAH is exposed to adrenal androgens at the critical time of sexual differentiation (9-12 weeks gestational age). Androgens masculinize external female genitalia causing genital ambiguity
Seen in classical 21OHD and 11β-hydroxylase deficiency CAH
- Clitoral enlargement
- Fusion & scrotalization of labial folds
- Phallus in the male position (d/t rostral migration of the urethral/vaginal perineal orifice)
Normal internal female genitalia:
Females with CAH do not have testis and therefore do not produce anti-Müllerian hormone (AMH), which is produced by the testicular Sertoli cells. Internal female structures are Müllerian derivatives and are not androgen responsive.
Postnatal effects and growth: Central precocious puberty
Deficient postnatal treatment in boys and girls results in continued exposure to excessive androgens
- Progressive penile/clitoral enlargement
- Premature pubic hair (pubarche), axillary hair, acne
- Rapid growth usually accompanied by premature epiphyseal maturation & closure (patient with CAH is a tall child but a short adult unless appropriate treatment is begun earlier in childhood)
- Impaired fertility
Signs of hyperandrogenism:
- Males:
- Male-pattern alopecia (temporal balding)
- Acne
- Females:
- Hirsutism: Excessive growth of coarse terminal hairs in androgen-dependent areas in women.
- Menstrual irregularities
- Polycystic Ovarian Syndrome (PCOS)
Behavioral masculinization:
- Reduced female gender satisfaction
- Reduced heterosexual interest in adulthood
- Gender dysphoria
- No effect on cognitive abilities
Reduced fertility:
- In females: D/t anovulation, secondary PCOS, irregular menses, non-suppressible serum progesterone levels, or an inadequate introitus)
- In males: Reduced sperm counts and low testosterone (as a result of small testes d/t suppression of gonadotropins)
Diagnosis
Diagnosis of CAH must be suspected in infants born with ambiguous genitalia.
Hormonal screening:
- 17-hydroxyprogesterone (17-OHP) blood levels (IOC for 21-hydroxylase deficiency)
- 11-deoxycortisol (IOC for 11β-hydroxylase deficiency)
ACTH stimulation test:
GOLD STANDARD for hormonal diagnosis: 250 μg cosyntropin IV, measuring levels of 17-OHP and Δ4 androstenedione at baseline and 60 min
Management
The primary goal of treating classic CAH is to reduce the excess adrenal androgen production and replace the deficient hormones, namely cortisol and aldosterone. Proper treatment will prevent both adrenal crisis and ongoing virilization
Glucocorticoid (GC) & mineralocorticoid (MC) replacement therapies:
Mainstays of treatment
- Glucocorticoid replacement: Life-long hydrocortisone (15-20 mg/m2/24hr orally in 3 divided doses)
- Mineralocorticoid replacement: Fludrocortisone (higher dose in infants)
Surgical management:
Indicated in significantly virilized females by the age of 2-6 months
Prenatal steroid therapy:
Indicated in pregnancies at risk (previously affected child). Steroid therapy is started as soon as pregnancy is diagnosed
- Dexamethasone (20 μg/kg): Suppress secretion of steroids by fetal adrenals and prevent virilization of external genitalia of affected females.
- Later chorionic villous biopsy is preformed to determine sex and genotype and therapy is continued only if fetus is female