Seventeen Alpha-hydroxylase Deficiency

Abstract

Seventeen alpha-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia in which defects in the biosynthesis of cortisol and sex steroid result in mineralocorticoid excess, hypokalemic hypertension and sexual abnormalities such as pseudohermaphroditism in males, and sexual infantilism in females. The disease is inherited in an autosomal recessive pattern, and is caused by mutations in the gene encoding cytochrome P450c17 (CYP17), which is the single polypeptide that mediates both 17alpha-hydroxylase and 17,20-lyase activities. We report the case of a 15-year-old patient with 17OHD who had a female phenotype but male karyotype (46,XY). The diagnosis was made based on classical clinical features, biochemical data and molecular genetic study. Two mutations were identified by polymerase chain reaction amplification and sequencing, including a S106P point mutation in exon 2 and a 9-bp (GACTCTTTC) deletion from nucleotide position 1519 in exon 8 of CYP17. The first of these mutations was found in the father and the second in the mother, and both have been previously reported in Asia. The patient's hypertension and hypokalemia resolved after glucocorticoid replacement and treatment with potassium-sparing diuretics. Sex hormone replacement was prescribed for induction of sexual development and reduction of the final height. Prophylactic gonadectomy was scheduled. In summary, 17OHD should be suspected in patients with hypokalemic hypertension and lack of secondary sexual development so that appropriate therapy can be implemented.

CYP17A1 Intron Mutation Causing Cryptic Splicing in 17α-Hydroxylase Deficiency

“…The suppression of aldosterone in 17OHD is variable [1], even within the same family [16]. Normal or even high aldosterone with suppressed renin has been reported [4], [10], [16]–[18]. The factors leading to detectable aldosterone in 17OHD are not known [19].…”

Syndromes of Mineralocorticoid Excess

“…The three adrenal cortex zones Z Glom, Z Fas, and Z Ret stand above the "column" of hormones that are produced in the respective zone. The steroidogenic enzymes on the left starting with P450scc (Desmolase) are listed in order for " vertical and horizontal reading," i.e., Desmolase converts cholesterol to pregnenolone, 3beta-OH-Steroid Dehydrogenase I/II convert pregnenolone to progesterone, 17-OH-Pregnenolone to 17-OH-Progesterone, and P450c11 converts deoxycorticosterone to 18-OH-Corticosterone and 11-Deoxycortisol to cortisol, etc deoxycorticosterone (DOC) (primary: DOC-secreting adrenocortical adenoma/ carcinoma [21][22][23][24] or secondary: 11beta-hydroxylase de fi ciency [25][26][27] , 17alpha-hydroxylase de fi ciency [28][29][30] , substances with high mineralocorticoid activity can lead to salt and water retention and consequently hypertension without causing hypernatremia.…”

“…Also, adrenal androgens are produced in excess in individuals with 11beta-hydroxylase de fi ciency compared with 17alpha-hydroxylase de fi ciency where they are de fi cient [25][26][27][28][29][30] . In patients with 17alpha-hydroxylase de fi ciency a persistent elevation of ACTH increases DOC and corticosterone levels and as a consequence affected patients will develop hypertension, hypokalemia, low aldosterone, and suppressed renin [28][29][30] . AME is caused by de fi ciency of the enzyme 11 b HSD2) [31][32][33] .…”

“…Cytochrome P450c17 enzyme complex catalyzes both 17-hydroxylase and 17,20 • lyase activity [ 25,[28][29][30] . Clinical fi ndings: pseudohermaphroditism (46, XY male), sexual infantilism • (46, XX female), varying degrees of hypertension and hypokalemic alkalosis.…”

Evaluation of plasma enzyme activities using gas chromatography–mass spectrometry based steroid signatures

“…The steroid metabolic pathways are involved in two major types of enzymes, cytochrome P450 and other steroid oxidoreductases. Many endocrine disorders can be attributed to defects in these enzymes that lead to a hormonal imbalance and serious consequence [4][5][6][7][8][9][10]. As an example, the enhanced androgenic activity by the conversion of testosterone to an active form, dihydrotestosterone (DHT), by 5␣-reductase is closely related to prostate diseases and male-pattern baldness [11][12][13].…”