Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene for the enzyme CYP17A1. It produces decreased synthesis of both cortisol and sex steroids, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild hypocortisolism, ambiguous genitalia in genetic males or failure of the ovaries to function at puberty in genetic females, and hypertension (respectively).
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 50,000 births.
The most common abnormal alleles of this condition impair both the 17α-hydroxylase activity and the 17,20-lyase activity of CYP17A1. Like other forms of CAH, 17α-hydroxylase deficiency 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 deficiency of prenatal and pubertal sex steroids.
CYP17A1 functions in steroidogenesis, where it converts pregnenolone and progesterone to their 17-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 17α-hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations in cortisol and sex steroid synthesis:
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 OMIM number for diseases arising from mutations of this gene is 202110
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: 17α-hydroxylase deficient CAH, and a distinct and even rarer 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. However, the clinical features of the two types of impairment are distinct enough that they are described separately in the following sections.
A few milder forms of this deficiency in genetic females have allowed relatively normal breast development and irregular menstruation. 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 these girls, the elevated blood pressure was the primary clinical problem.
17α-Hydroxylase deficiency in genetic males (XY) results in moderate to severe reduction of fetal testosterone production by both 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 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 testoserone deficiency.
The sex steroid deficiency produces effects similar to 17α-hydroxylase deficiency. Severely affected genetic females (XX) are born with normal internal and external genitalia and there are no clues to abnormality until adolescence, when both the androgenic and estrogenic signs (e.g., breasts and pubic hair) of puberty fail to occur. Gonadotropins are high and the uterus infantile in size. The ovaries may contain enlarged follicular cysts, and ovulation may not occur even after replacement of estrogen.
Hypertension and mineralocorticoid excess is treated with glucocorticoid replacement, as in other forms of CAH.
Most genetic females with both forms of the deficiency will need replacement estrogen to induce puberty. Most will also need periodic progestin to regularize menses. Fertility is usually reduced because egg maturation and ovulation is poorly supported by the reduced intra-ovarian steroid production.
The most difficult management decisions are posed by the more ambiguous genetic (XY) males. Most who are severely undervirilized, looking more female than male, are raised as females with surgical removal of the nonfunctional testes. If raised as males, a brief course of testosterone can be given in infancy to induce growth of the penis. Surgery may be able to repair the hypospadias. The testes should be salvaged by orchiopexy if possible. Testosterone must be replaced in order for puberty to occur and continued throughout adult life.