<unk> -hydroxylase converts pregnenolone and progesterone to their<unk> -hydroxy forms. It corresponds to the red arrows in this reaction scheme. This form of CAH results from<unk>  of the enzyme<unk> -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 most common abnormal alleles of this condition impair both the<unk> -hydroxylase activity and the 17,20-lyase activity of CYP17A1. Like other forms of CAH,<unk> -hydroxylase<unk>  impairs the efficiency of cortisol synthesis, resulting in high levels of ACTH secretion and hyperplasia of the adrenal glands. Clinical effects of this condition include overproduction of mineralocorticoids and<unk>  of prenatal and pubertal sex steroids. CYP17A1 functions in steroidogenesis, where it converts pregnenolone and progesterone to their<unk> -hydroxy forms. The enzyme itself is attached to the smooth endoplasmic reticulum of the steroid-producing cells of the adrenal cortex and gonads. CYP17A1 functions as both a<unk> -hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations in cortisol and sex steroid synthesis: * As<unk> -hydroxylase it mediates pregnenolone →<unk> -hydroxypregnenolone * and progesterone →<unk> -hydroxyprogesterone. * As 17,20-lyase it mediates<unk> -hydroxypregnenolone → DHEA. * An expected second 17,20-lyase reaction <unk> -hydroxyprogesterone → androstenedione) is mediated so inefficiently in humans as to be of no known significance. The hydroxylase reactions are part of the synthetic pathway to cortisol as well as sex steroids, but the lyase reaction is only necessary for sex steroid synthesis. Different alleles of the CYP17A1 gene result in enzyme molecules with a range of impaired or reduced function that produces a range of clinical problems. The dual enzyme activities were for many decades assumed to represent two entirely different genes and enzymes. Thus, medical textbooks and nosologies until quite recently described two different diseases:<unk> -hydroxylase deficient CAH, and a distinct and even rarer defect of sex steroid synthesis termed 17,20-lyase<unk>  (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. However, the clinical features of the two types of impairment are distinct enough that they 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 persons with<unk> -hydroxylase<unk>  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 clue distinguishing the more complete<unk> -hydroxylase<unk>  from the 17,20-lyase<unk> , which only affects the sex steroids. 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 50-100-fold elevations of corticosterone have enough weak glucocorticoid activity to prevent glucocorticoid<unk>  and adrenal crisis. Sex steroid effects Genetic XX females affected by total<unk> -hydroxylase<unk>  are born with normal female internal and external anatomy. At the expected time of puberty neither the adrenals nor the ovaries can produce sex steroids, so neither breast development nor pubic hair appear. Investigation of delayed puberty yields elevated gonadotropins and normal karyotype, while imaging confirms the presence of ovaries and an infantile uterus. Discovery of hypertension and hypokalemic alkalosis usually suggests the presence of one of the proximal forms of CAH, and the characteristic mineralocorticoid elevations confirm the specific diagnosis. Milder forms of this<unk>  in genetic females allow some degree of sexual development, with variable reproductive system dysregulation that can include incomplete Tanner scale development, retrograde sexual development, irregular menstruation, early menopause, or – in very mild cases – no physical symptoms beyond infertility. 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.<unk> -hydroxylase<unk>  in genetic males (XY) results in moderate to severe reduction of fetal testosterone production by adrenals 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<unk> . 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<unk>  or insensitivity. Fertility is impaired in those with more than minimal testosterone<unk> .
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency
Primary pigmented nodular adrenocortical disease
Lipoid congenital adrenal hyperplasia
Pituitary ACTH hypersecretion
Cortisone reductase deficiency