Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
 | This article needs editing to comply with Wikipedia's Manual of Style. In particular, it has problems with does not follow MEDMOS. (October 2021) |
| 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 of
Pathophysiology
This form of CAH results from deficiency of the
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 of
CYP17A1 functions in
- As 17α-hydroxylase it mediates 17α-hydroxypregnenolone
- and 17α-hydroxyprogesterone.
- As 17,20-lyase it mediates 17α-hydroxypregnenolone → DHEA.
- An expected second 17,20-lyase reaction (17α-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 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 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.[7] 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,
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.[8]
Sex hormone effects
Genetic females affected by total 17α-hydroxylase deficiency are born with normal female primary sex characteristics. At the expected time of puberty neither the adrenals nor the ovaries can produce sex hormones, so neither breast development nor pubic hair appear. Testing yields elevated gonadotropins and normal karyotype, while imaging confirms the presence of ovaries and an underdeveloped 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.[citation needed]
Milder forms of this deficiency 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.[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 not ovulation 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 fetal
17,20-lyase deficiency
 |
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.
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]
Treatment
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.[citation needed]
See also
- Cytochrome b5 deficiency
- Inborn errors of steroid metabolism
- Congenital adrenal hyperplasia
- Isolated 17,20-lyase deficiency
- Disorders of sexual development
- CYP17A1 (17α-hydroxylase/17,20-lyase)
References
- ^ Uwaifo, Gabriel (Feb 24, 2023). "C-17 Hydroxylase Deficiency". Medscape. Retrieved Feb 8, 2024.
- ^ a b "17 alpha-hydroxylase/17,20-lyase deficiency: MedlinePlus Genetics". medlineplus.gov. Retrieved 2024-02-09.
- ^ Online Mendelian Inheritance in Man (OMIM): CYTOCHROME P450, FAMILY 17, SUBFAMILY A, POLYPEPTIDE 1; CYP17A1 - 609300
- S2CID 20706555.
- PMID 12645864.
- ^ Online Mendelian Inheritance in Man (OMIM): ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 17-ALPHA-HYDROXYLASE DEFICIENCY - 202110
- PMID 22072737.
- ^ a b C-17 Hydroxylase Deficiency Medication at eMedicine
- PMID 15713706.
- PMID 8855840.
- PMID 2808364.
- PMID 29710837.
Further reading
- Krone, Nils; Dhir, Vivek; Ivison, Hannah E.; Arlt, Wiebke (2007). "Congenital adrenal hyperplasia and P450 oxidoreductase deficiency". Clinical Endocrinology. 66 (2): 162–72. S2CID 26037794.