and
progesterone to their 17α-hydroxy forms. It corresponds to the red arrows in this reaction scheme. This form of CAH results from deficiency of the
enzyme 17α-hydroxylase (also called
CYP17A1). It accounts for less than 5% of the cases of
congenital adrenal hyperplasia and is inherited in an
autosomal recessive manner with a reported incidence of about 1 in 1,000,000 births. The dual enzyme activities were for many decades assumed to represent two entirely different genes and enzymes. Thus, medical textbooks and diagnostic manuals formerly described two different diseases:
17α-hydroxylase deficient CAH, and a distinct and more rare defect of sex steroid synthesis termed
17,20-lyase deficiency (which is not a form of CAH). In the last decade it has become clearer that the two diseases are different forms of defects of the same gene. The clinical features of the two types of impairment are described separately in the following sections.
Mineralocorticoid effects The adrenal cortex is hyperplastic and overstimulated, with no impairment of the mineralocorticoid pathway. Consequently, levels of DOC,
corticosterone, and
18-hydroxycorticosterone are elevated. Although these precursors of
aldosterone are weaker mineralocorticoids, the extreme elevations usually provide enough volume expansion, blood pressure elevation, and potassium depletion to suppress
renin and aldosterone production. Some people with 17α-hydroxylase deficiency develop
hypertension in infancy, and nearly 90% do so by late childhood. The low-renin
hypertension is often accompanied by
hypokalemia due to urinary potassium wasting and
metabolic alkalosis. These features of mineralocorticoid excess are the major clinical clues distinguishing the more complete 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the sex hormones. Treatment with glucocorticoid suppresses ACTH, returns mineralocorticoid production toward normal, and lowers blood pressure.
Glucocorticoid effects Although production of cortisol is too inefficient to normalize ACTH, the 50- to 100-fold elevations of
corticosterone have enough weak
glucocorticoid activity to prevent glucocorticoid deficiency and
adrenal crisis. Evidence suggests that only 5% of normal enzyme activity may be enough to allow at least the physical changes of female puberty, if not
ovulation and fertility. In women with mild cases, elevated blood pressure and/or infertility is the presenting clinical problem. 17α-hydroxylase deficiency in genetic males results in moderate to severe reduction of fetal
testosterone production by adrenal glands and testes.
Undervirilization is variable and sometimes complete. The appearance of the external
genitalia ranges from normal female to ambiguous to mildly underdeveloped male. The most commonly described phenotype is a small
phallus,
perineal hypospadias, small blind pseudovaginal pouch, and intra-abdominal or
inguinal testes.
Wolffian duct derivatives are hypoplastic or normal, depending on degree of testosterone deficiency. Some of those with partial virilization develop
gynecomastia at puberty even though masculinization is reduced. The presence of hypertension in the majority distinguishes them from other forms of partial androgen deficiency or
insensitivity. Fertility is impaired in those with more than minimal testosterone deficiency. ==17,20-lyase deficiency==