17-Hydroxylase Deficiency Syndrome

17-Hydroxylase (17-OH) deficiency syndrome is a rare genetic disorder of steroid biosynthesis that causes decreased production of glucocorticoids and sex steroids and increased synthesis of mineralocorticoid precursors. It is a rare form of congenital adrenal hyperplasia (CAH) resulting from loss-of-function mutations involving the CYP17 gene.[1]

This syndrome is characterized by both of the following:

• Decreased production of glucocorticoids and sex steroids, resulting in sexual infantilism in 46,XX females and ambiguous genitalia in 46,XY males
• Increased synthesis of mineralocorticoid precursors, resulting in varying degrees of hypertension and hypokalemia

Patients are usually diagnosed with this condition during an evaluation of delayed puberty, absent secondary sexual characteristics, or primary amenorrhea. Although patients with 17-hydroxylase deficiency are cortisol deficient, they do not typically have adrenal insufficiency or experience adrenal crises. Precursor hormones such as corticosterone are elevated, have glucocorticoid activity, and are adequate to prevent adrenal insufficiency.

Exogenous glucocorticoid therapy is the treatment of choice and suppresses adrenocorticotropic hormone (ACTH) secretion, decreases 11-DOC and corticosterone levels, and normalizes serum potassium and blood pressure. Some patients may have persistent hypertension and require additional antihypertension therapy. Prognosis is generally good-to-excellent with adequate glucocorticoid therapy and monitoring.

At puberty, patients require sex steroid replacement for development of secondary sexual characteristics as well as cyclic menstrual bleeding in 46,XX females.

For patient education resources, see the Women's Health Center, as well as Amenorrhea.

Anatomically, the adrenal gland can be divided into the following three zones:

• Zona glomerulosa, which produces predominately mineralocorticoid

• Zona fasciculata, which produces predominately glucocorticoid

• Zona reticularis, which produces predominately androgens

For convenience, think of the zona glomerulosa as the first endocrine organ and the zonae fasciculata and reticularis collectively as a second separate endocrine organ, as distinguished by distinct control systems.

Aldosterone (mineralocorticoid) synthesis and secretion is regulated via the renin-angiotensin system, which is responsive to the electrolyte balance state and plasma volume. Aldosterone secretion is also directly stimulated by high serum potassium concentrations. In contrast, cortisol synthesis and secretion is regulated by adrenocorticotropic hormone (ACTH), which stimulates the enzyme P-450scc (20, 22 desmolase) with subsequent increased production of all adrenal steroids in both the zona fasciculata and zona reticularis.

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of adrenal steroid biosynthesis in which one of the enzymes necessary for cortisol production has deficient activity. Decreased serum cortisol levels stimulate ACTH release via negative feedback. The adrenal glands undergo hypertrophy, apparently due to ACTH-stimulated production of insulinlike growth factor-2 (IGF-2). Increased ACTH secretion also results in overproduction of both the adrenal steroids preceding the missing enzyme and those that do not require the missing enzyme (ie, build-up of compounds both before the block and "sideways" from the block). See following image. Treatment with exogenous glucocorticoid decreases ACTH secretion and subsequent suppression of overproduced steroids.

Cytochrome P450c17, an enzyme complex present in Leydig cells, ovarian follicles, and the adrenal zonae fasciculata and reticularis, catalyzes both 17-hydroxylase and 17,20 lyase activity. As might be expected from its location, P450c17 defects affect both adrenal and gonadal steroid production. P450c17 is the product of the cytochrome P45017 alpha gene (CYP17A1), and specific mutations of this gene cause varying degrees of partial-to-severe isolated 17-hydroxylase deficiency, isolated 17,20 lyase deficiency, or combined deficiencies.[2, 3, 4, 5, 6]

More than 100 different genetic mutations of the CYP17A1 gene have been described worldwide in patients with 17-hydroxylase deficiency[6, 7, 8, 9, 10, 11] For example, among the Chinese Han, two CYP17A1 mutations, D487-S488-F489 deletion and TAC329AA, account for the majority of 17-hydroxylase deficiency cases.[7, 12] Different CYP17A1 mutations have been found in other Chinese cases, including novel nonsense mutations R449C and L209P.[8] By contrast, in a Brazilian cohort of 19 families with 17-hydroxylase deficiency,[9] 7 different CYP17 mutations were found among 24 subjects. However, two mutations accounted for most cases: W406R (50%) and R362C (32%). In these families, phenotypic features varied among the subjects and did not correlate with the CYP17 genotype.

A rare cause of 17-hydroxylase deficiency syndrome, first reported in 2004, is autosomal recessive P450 oxidoreductase (POR) deficiency. POR is an obligate electron donor for all microsomal P450 enzymes, including P450c17 (17α-hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450 aro (aromatase). POR deficiency can affect multiple steroidogenic pathways and have variable presentations depending on relative degrees of impaired enzyme activity. Drug metabolism may also be affected in these patients as many drugs are metabolized by hepatic P450s.[13, 14, 15, 16]

C-17α-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog)[1] ; see first image below. Thus, absence of this enzyme impairs all sex steroid and cortisol production (see second image below). Low levels of cortisol result in increased ACTH stimulation of steroids prior to the 17-hydroxylase step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone (compound B).

Hypogonadism occurs as a result of deficient sex steroid production. DOC mineralocorticoid activity causes sodium retention, plasma volume expansion, hypertension, hypokalemia, and decreased renin and aldosterone levels in most untreated patients with 17-hydroxylase deficiency.

17-Hydroxylase (17-OH) deficiency syndrome is caused by mutations in the CYP17A1 gene located on chromosome 10q24.3.[17] More than 100 mutations have been identified[18] ; however, populations in which 17-OH deficiency syndrome is more prevalent, such as Brazilians,[9] Canadian Mennonites,[19] Dutch Frieslanders,[19] Japanese, Koreans,[10] and Chinese[20] have specific reoccurring mutations thought to be due to founder effect.[18]

A small number of CYP17A1 gene mutations have been found to cause isolated 17,20-lyase deficiency, which is characterized by abnormal sexual development without hypertension or hypokalemia. These mutations alter a region of the CYP17A1 protein that plays a role in the enzyme's 17,20-lyase function but not its 17α-hydroxylase function. As a result, 17,20-lyase activity is severely reduced but 17α-hydroxylase activity is normal.[21]

Incidence

17-Hydroxylase deficiency is a rare cause of congenital adrenal hyperplasia (CAH), accounting for less than 1% of cases and occurring in 1 in 50,000 people globally.[22] Over 90% of individuals with CAH have 21-hydroxylase deficiency.[18] The incidence of classic 21-hydroxylase deficiency affects 1 in 16,000 live births. Milder (nonclassic) 21-hydroxylase deficiency is estimated to occur in 1 in 1,000 births and even more frequently in populations of specific ethnicities, such as Ashkenazi Jews (1 in 27), Hispanics (1 in 53), Yugoslavs (1 in 62) and Italians (1 in 300).[22, 23] The second most common type, 11-β -hydroxylase deficiency, represents 5-8% of CAH cases has an incidence of about 1 in 100,000 individuals but is 20 times higher in Moroccan Jews.[22] (See C-11 Hydroxylase Deficiency.)

17-Hydroxylase deficiency occurs worldwide. However, there have been fewer than 200 cases reported in the literature and most of these reported cases were either isolated or occurred in small clusters. Examples include Turkey, where the reported incidence was 1 in 273 patients with CAH over a 25-year period[24] ; Brazil, where 16 cases were reported over a 10-year period[9] ; and Puerto Rico, where 1 case was reported.[25] New cases of 17-hydroxylase deficiency continue to be reported, most recently in Korea and China.[10, 11, 20]

Age

A diagnosis of 17-hydroxylase deficiency may be suspected in infancy or childhood when hypokalemia and hypertension are found in association with either ambiguous genitalia or in an apparent female patient with a hernia or inguinal mass.[20] However, many patients may go undiagnosed until adolescence or young adulthood. Karyotypic 46,XY patients may be undiagnosed until puberty, having been raised as females, and present to an endocrinologist or nephrologist for evaluation due to lack of secondary sexual characteristics and varying degrees of hypertension and hypokalemia. Similarly, 46,XX patients are usually diagnosed upon presentation of delayed puberty or lack of menses, along with hypertension and hypokalemia.[26]

Prognosis for patients with 17-hydroxylase (17-OH) deficiency syndrome is usually good-to-excellent with adequate glucocorticoid therapy and monitoring. Patients rarely, if ever, have adrenal crises. Sex steroid replacement promotes development of secondary sexual characteristics in both sexes and cyclic menstrual bleeding in females. Fertility may be impaired in both male and female patients with severe deficiency.[27]

Corticosterone has some glucocorticoid activity; elevated levels (ie, 50-100 times normal) are adequate to prevent adrenal insufficiency. Thus, these patients do not have hypoglycemia, hypotension, or difficulties dealing with infections, stress, or surgical procedures. These patients also experience no virilization or accelerated prepubertal growth as is typical in more common types of congenital adrenal hyperplasia (CAH) that result from lack of sex steroids.

Most patients have some degree of hypokalemia and hypertension; blood pressure elevations range from mild to severe. Although 10-15% may have no hypertension or hypokalemia at presentation, patients may present with malignant hypertension or with severe, symptomatic hypokalemia. Hypertension sometimes may persist for months to years in older or more severely affected individuals, necessitating additional antihypertension therapy.

Complications

Despite sex steroid replacement, patients with 17α-hydroxylase/17,20-lyase deficiency develop hypergonadotropic hypogonadism and infertility due to the decreased enzymatic activity of CYP17A1.

Irreversible defects in steroidogenesis may lead to impaired spermatogenesis and folliculogenesis, and women are unable to conceive spontaneously or via endocrinological intervention. A single report of pregnancy in a patient with partial 17α-hydroxylase/17,20-lyase deficiency, resulted in the live birth of triplets following in vitro fertilization.[27] Two additional live births resulting from fertility therapy have been reported.[28, 29]

Although normal T production in males with 17OHD is possible, there are no reports of male fertility. Milder cases of 17OHD might be assumed to be “idiopathic hypospadias” if not evaluated thoroughly. Consequently, the capacity of men with partial 17OHD to reproduce might be higher than assumed from more severe cases.[27]

In general, patients with 17-hydroxylase (17-OH) deficiency have no history of adrenal insufficiency nor adrenal crisis, presumably due to elevated levels of corticosterone. Patients may have a history of hypertension; alternatively, hypertension may be the presenting complaint. Both the age of onset and degree of severity of hypertension seem to vary between patients.[3]

46,XX karyotype with P450c17 deficiency

Virilization and development of ambiguous genitalia do not occur in 46,XX patients with 17-hydroxylase deficiency.

Unless hypertension is discovered, females may have no historical complaints or findings until puberty.

The ovaries are unable to secrete either androgens or estrogens necessary for sexual maturation, and the adrenal glands cannot secrete androgens necessary for pubic and axillary hair growth. Consequently, adolescent or older females present with complaints of delayed puberty,[3] primary amenorrhea,[30] and lack of secondary sexual characteristics.

46,XY karyotype with P450c17 deficiency

Under-masculinization always occurs in 46,XY individuals with complete P450c17 deficiency.[3] The genitals of such patients vary from phenotypic female to ambiguous male genitalia. Males with phenotypic female genitalia may go undetected until puberty, at which time they present with complaints similar to those of 46,XX patients.

The diagnosis may be suspected in an apparent female infant or young child with a history of an abdominal hernia, inguinal mass, or otherwise unexplained hypertension.

Mildly to severely elevated blood pressure may be the primary finding in patients with 17-hydroxlase deficiency syndrome.

46,XX karyotype with P450c17 deficiency

Affected 46,XX individuals have phenotypic female normal external and internal female differentiation.

Adolescent and older women may exhibit sexual infantilism and little or no pubic or axillary hair.

The first described female patient presented with hypertension, hypokalemia, no breast development, primary amenorrhea, and lack of pubic and axillary hair.

Internally, patients have a small prepubertal uterus and may have multicystic ovaries, presumably from gonadotropic stimulation.

46,XY karyotype with P450c17 deficiency

Genitals of affected 46,XY individuals vary from phenotypic female to ambiguous male genitalia.

Gynecomastia has been reported in a male patient with ambiguous genitalia.

The patient may present as an otherwise phenotypic normal female; however secondary sexual characteristics are missing. Closer physical examination reveals the vagina to be a blind pouch, and the patient lacks internal genitalia.

Testes may be undescended or located in the inguinal canal.

Histology of the testes reveals atopic tubules, Sertoli cells, and Leydig cell hyperplasia.

Although rarely diagnosed in younger children, an abdominal hernia or inguinal mass in a phenotypic female infant or child, especially if combined with hypertension, suggests a diagnosis of 17-hydroxylase deficiency.

P450 oxidoreductase deficiency

Patients with P450 oxidoreductase (POR) deficiency have varying degrees of adrenal insufficiency and genital anomalies. Skeletal malformations, including craniosynostosis, radio-ulnar synostosis, midface hypoplasia, and bowed femurs (Antley-Bixler syndrome), may be caused by fibroblast growth factor 2 receptor mutations, but have also been reported in patients with POR deficiency. Genital anomalies are found in both male and female patients with POR deficiency. Affected males may be ambiguous as would be expected from the low levels of sex steroids. However, affected females with POR can actually present with severe virilization. Virilization in such affected 46 XX females may be due to an alternative androgen pathway involving dihydrotestosterone synthesis, but the exact mechanism remains incompletely explained.[13, 14, 15]

Male and female patients have no biochemical differences.

All steroids requiring 17-hydroxylase (17-OH) activity for their production are found in very low concentrations. 17-Hydroxypregnenolone (17-OH Preg), 17-hydroxyprogesterone (17-OH Prog; see 17-Hydroxyprogesterone, Serum and 17-Hydroxyprogesterone, Urine), 11-deoxycortisol (compound S), cortisol, dehydroepiandrosterone (DHEA), androstenedione, and testosterone are all decreased or absent. The urinary metabolites 17-hydroxylase corticosteroid and 17-ketosteroid also are decreased or absent.

Serum estrogens and urinary estrogens are low.

Pregnenolone and progesterone levels are somewhat elevated; diagnosis is confirmed by markedly elevated levels of 11-deoxycorticosterone (11-DOC) and corticosterone.

Aldosterone and plasma renin concentrations are usually low. DOC-mediated mineralocorticoid activity causes sodium retention and plasma volume expansion, with subsequent suppressed renin and aldosterone levels in most untreated patients.

Within the pituitary, adrenocorticotropic hormone (ACTH) levels are elevated due to lack of cortisol secretion. The gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are elevated secondary to deficient sex steroid production by the gonads.

17-Hydroxylase deficiency is inherited as an autosomal recessive trait similar to other forms of congenital adrenal hyperplasia (CAH). However, 17-hydroxylase is not linked to the human leukocyte antigen (HLA) system. Detection of heterozygote carriers is difficult and requires biochemical rather than genetic criteria.

Unstimulated levels of 11-deoxycorticosterone (11-DOC) and corticosterone may be somewhat elevated in heterozygotes, and these individuals may have an exaggerated response to ACTH stimulation.

Prenatal diagnosis of an affected infant is possible by measuring amniotic fluid concentrations of adrenal steroids or maternal urine steroid metabolite excretion.[33]

Exogenous glucocorticoid therapy is the treatment of choice. Oral hydrocortisone (or other glucocorticoid) suppresses adrenocorticotropic hormone (ACTH) secretion and decreases 11-deoxycorticosterone (11-DOC) and corticosterone levels.

Potassium and blood pressure abnormalities resolve after suppression of excessive mineralocorticoid activity, although some hypertension may persist for months to years in older or more severely affected individuals. Patients with this condition require additional antihypertension therapy. Additionally, estrogen therapy has been suggested to worsen hypertension in a few patients.[3]

At puberty, male patients require sex steroid replacement (ie, testosterone). Female patients require cyclic estrogen-progesterone therapy. These therapies promote development of secondary sexual characteristics in both sexes and cyclic menstrual bleeding in 46,XX females.

Adults with 17-hydroxylase deficiency

Although extensive literature and experience regarding treatment of pediatric patients is available, little has been published regarding treatment of adults with congenital adrenal hormone deficiencies. Certainly, no consensus or published guidelines are available regarding types, dosages, or timing of steroid replacement in adult patients.[34, 35]

One survey in the United Kingdom demonstrated that the most widely used glucocorticoid in adult patients was hydrocortisone, followed by dexamethasone and prednisolone. Sixty percent of physicians surveyed used larger doses of glucocorticoids at night (reverse circadian pattern) to achieve adrenocorticotropic hormone (ACTH) suppression, and only 16% of treating physicians used body weight or surface area to determine dosage.[35]

Adult patients must be continuously and carefully treated, using body size or weight-related dosages (in a manner analogous to pediatric treatment) to avoid extremes of overtreatment and undertreatment.

Perform a orchidectomy in 46,XY males who are raised as females; intra-abdominal testes carry a high risk of tumorous and malignant transformation.[12]

Manifestations of 17OHD in 46,XX females include ovarian cysts and painful cyst rupture which may require surgical intervention.[32]

Exogenous glucocorticoid therapy suppresses adrenocorticotropic hormone (ACTH) secretion, decreases 11-DOC and corticosterone levels, and normalizes serum potassium and BP. Hydrocortisone is the drug of choice for infants and children. Longer-acting preparations (eg, prednisone, dexamethasone) are difficult to titrate and can lead to overtreatment and growth suppression.

Class Summary

Exogenous glucocorticoid therapy suppresses adrenocorticotropic hormone (ACTH) secretion, decreases 11-deoxycorticosterone (11-DOC) and corticosterone levels, and normalizes serum K levels and blood pressure. Patients tend to respond to smaller doses of glucocorticoids than those required in other forms of congenital adrenal hyperplasia, possibly due to the glucocorticoid activity of endogenous corticosterone. Dosages are somewhat empirical and must be individualized based on clinical findings, growth, skeletal maturation, and hormonal data, including monitoring of 11-DOC and corticosterone levels.

Hydrocortisone (Hydrocortone, A-Hydrocort)

Hydrocortisone is the drug of choice for infants and children. Longer-acting preparations (eg, prednisone, dexamethasone) are difficult to titrate and can lead to overtreatment and growth suppression.