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| Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency | |
|---|---|
| Specialty | Endocrinology,obstetrics and gynaecology,medical genetics  |
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form ofcongenital adrenal hyperplasia (CAH) resulting from a mutation in thegeneCYP17A1, which produces theenzyme 17α-hydroxylase.[1][2] It causes decreased synthesis ofcortisol andsex hormones, with resulting increase inmineralocorticoid production. Thus, common symptoms include mildcortisol deficiency,ambiguous genitalia in men oramenorrhea at puberty in women, andhypokalemichypertension.[3] However, partial (incomplete) deficiency often has inconsistent symptoms between patients,[4] and affected women may be asymptomatic except forinfertility.[5]
This form of CAH results from deficiency of theenzyme17α-hydroxylase (also calledCYP17A1). It accounts for less than 5% of the cases ofcongenital adrenal hyperplasia and is inherited in anautosomal recessive manner with a reported incidence of about 1 in 1,000,000 births.[2]
The most common forms 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 ofcortisol synthesis, resulting in high levels ofACTH secretion andhyperplasia of the adrenal glands. Clinical effects of this condition include overproduction ofmineralocorticoids and deficiency of prenatal andpubertalsex hormones.[citation needed]
CYP17A1 functions insteroidogenesis, where it convertspregnenolone andprogesterone to their 17α-hydroxy forms. The enzyme itself is attached to the smoothendoplasmic reticulum of the steroid-producing cells of theadrenal cortex andgonads. CYP17A1 functions as both a 17α-hydroxylase and a 17,20-lyase. The dual activities mediate three key transformations incortisol andsex hormone synthesis:[citation needed]
The hydroxylase reactions are part of the synthetic pathway to cortisol as well as sex hormones, but the lyase reaction is only necessary for sex hormone 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.[6]
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 termed17,20-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.[7] The clinical features of the two types of impairment are described separately in the following sections.
The adrenal cortex is hyperplastic and overstimulated, with no impairment of the mineralocorticoid pathway. Consequently, levels of DOC,corticosterone, and18-hydroxycorticosterone are elevated. Although these precursors ofaldosterone are weaker mineralocorticoids, the extreme elevations usually provide enough volume expansion, blood pressure elevation, and potassium depletion to suppressrenin and aldosterone production. Some people with 17α-hydroxylase deficiency develophypertension in infancy, and nearly 90% do so by late childhood. The low-reninhypertension is often accompanied byhypokalemia due to urinary potassium wasting andmetabolic 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.[8]
Although production of cortisol is too inefficient to normalize ACTH, the 50- to 100-fold elevations ofcorticosterone have enough weakglucocorticoid activity to prevent glucocorticoid deficiency andadrenal crisis.[8]
Genetic females affected by total 17α-hydroxylase deficiency are born with normal female primary sex characteristics. At the expected time ofpuberty neither the adrenals nor the ovaries can produce sex hormones, so neither breast development nor pubic hair appear. Testing yields elevatedgonadotropins and normal karyotype, while imaging confirms the presence of ovaries and an underdeveloped uterus. Discovery of hypertension and hypokalemicalkalosis usually suggests the presence of one of the proximal forms of CAH, and the characteristic mineralocorticoid elevations confirm the specific diagnosis.[citation needed]
Milder forms of this deficiency in genetic females allow some degree of sexual development, with variable reproductive system dysregulation that can include incompleteTanner scale development, retrograde sexual development, irregular menstruation, early menopause, or – in very mild cases – no physical symptoms beyond infertility.[9][10][11]Evidence suggests that only 5% of normal enzyme activity may be enough to allow at least the physical changes of female puberty, if notovulation and fertility.[citation needed] 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 fetaltestosterone production by adrenal glands and testes.Undervirilization is variable and sometimes complete. The appearance of the externalgenitalia ranges from normal female to ambiguous to mildly underdeveloped male. The most commonly described phenotype is a smallphallus,perinealhypospadias, small blind pseudovaginal pouch, and intra-abdominal oringuinal testes.Wolffian duct derivatives are hypoplastic or normal, depending on degree of testosterone deficiency. Some of those with partial virilization developgynecomastia at puberty even though masculinization is reduced. The presence of hypertension in the majority distinguishes them from other forms of partial androgen deficiency orinsensitivity. Fertility is impaired in those with more than minimal testosterone deficiency.[citation needed]
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A very small number of people have reportedly had an abnormal allele that resulted primarily in a reduction of 17,20-lyase activity, rather than both the hydroxylase and lyase activities as described above.[12] In these people the defect had the effect of an isolated impairment ofsex steroid (e.g., DHEA in the adrenal, but also gonadal testosterone and estrogens) synthesis, whereasmineralocorticoid (e.g., aldosterone) andglucocorticoid (e.g., cortisol) levels remain normal.[citation needed]
Normal aldosterone level can be attributed to the fact that aldosterone is independent of hypothalamus-pituitary axis feedback system, being mainly controlled by the level of serum potassium. Because of the normal aldosterone level, hypertension is not expected.
Normal cortisol level can be explained by the strong negative feedback mechanism of cortisol on hypothalamus-pituitary axis system. That is, in the beginning, 17,20-lyase deficiency will block synthesis of sex steroid hormones, forcing the pathways to produce more cortisol. However, the initial excess of cortisol is rapidly corrected by negative feedback mechanism—high cortisol decreases secretion of adrenocorticotropic hormone (ACTH) from zona fasciculata of adrenal gland. Thus, there is no mineralocorticoid overproduction. Also, there is no adrenal hyperplasia.[citation needed]
It has also been observed in patients that the adrenocorticotropic hormone (ACTH) level remains in the normal range. The reason for this is still unclear.
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 the androgenic and estrogenic signs (e.g., breasts and pubic hair) of puberty either fails to occur or is abnormal. 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.[citation needed]
Hypertension and mineralocorticoid excess is treated withglucocorticoid 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 byorchiopexy if possible. Testosterone must be replaced in order for puberty to occur and continued throughout adult life.[citation needed]