c

Anatomically, the adrenal gland can be divided into the following 3 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.

Normal adrenal steroid biosynthesis results in 3 products: mineralocorticoids (aldosterone), glucocorticoids (cortisol), and androgens
(androstenedione). Cortisol production is regulated by feedback with adrenocorticotropic hormone (ACTH). ACTH stimulates the enzyme
P-450scc (20,22 desmolase), with subsequently increased production of all adrenal steroids.

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. c

Ñepresentation of typical congenital adrenal hyperplasia (CAH). This example shows a deficiency in both the mineralocorticoid and
glucocorticoid pathways. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback.
Increased ACTH secretion causes overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the
missing enzyme. The example depicts a deficiency of 21-hydroxylase, resulting in deficient mineralocorticoid and glucocorticoid
production and excessive androgen production.

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 (J
), 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.1,2,3,4,5

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 (17 Į -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.6,7,8,9
C-17 Į -hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog);
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).

c
C-17r-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-
hydroxyprogesterone (17-OH Prog). Absence of C-17r-hydroxylase impairs all sex steroid and cortisol production. Low levels of cortisol
result in increased adrenocorticotropic hormone (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.

c
^raphic illustration of deficiency. Absence of C-17r-hydroxylase impairs all sex steroid and cortisol production.

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.
In order to better define the molecular basis of 17-hydroxylase deficiency, genetic analysis was performed on 19 families with 17-hydroxylase deficiency.10 Seven
different J
 mutations were found among 24 subjects. However, 2 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 J
 genotype. c
©requency
International

Approximately 80-90% of individuals with CAH have 21-hydroxylase deficiency. The incidence of classic 21-hydroxylase deficiency varies from 1 in 5000-15,000
live births in white populations to 1 in 300-700 in the Alaskan Yupik population. The second most common type of CAH, 11-ȕ -hydroxylase deficiency, has an
incidence of about 1 in 100,000 (see C-11 Hydroxylase Deficiency). 17-hydroxylase deficiency is probably even more rare. Some estimate the occurrence of 17-
hydroxylase deficiency at approximately 1 case per 50,000 individuals.

17-hydroxylase deficiency occurs worldwide. However, individuals with severe, confirmed 17-hydroxylase deficiency are rare, and most reported cases were
isolated or occurred in small clusters. Examples include Turkey, where the reported incidence was 1 of 273 patients with CAH over a 25-year period;11 Brazil,
where 16 cases were reported over a 10-year period;10 ; and Puerto Rico, where 1 case was reported.12

ortality/orbidity
Although cortisol-deficient, patients do not have adrenal insufficiency or experience adrenal crises. Corticosterone has some glucocorticoid activity; and 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 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.

Age
Female patients are usually diagnosed upon presentation of delayed puberty or lack of menses. Males may go undiagnosed until puberty. These boys are usually
raised as females and present to an endocrinologist for evaluation of lack of secondary sexual characteristics. Diagnosis may be suspected earlier in an infant with
ambiguous genitalia or in an apparent female patient with a hernia or inguinal mass, hypertension, and hypokalemia.
Clinical

History
In general, patients with 17-hydroxylase (17-OH) deficiency have no history of adrenal insufficiency or adrenal crisis, presumably due to elevated levels of
corticosterone (see Mortality/Morbidity). 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.2

„ Females with P450c17 deficiency

Y Virilization and development of ambiguous genitalia do not occur in 46,XX patients with 17-hydroxylase deficiency.
Y Unless hypertension is discovered, females may have no historical complaints or findings until puberty.
Y 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,2 ) primary amenorrhea,13 , and lack of secondary sexual characteristics.
„ Males with P450c17 deficiency
Y Under-masculinization always occurs in 46,XY individuals with complete P450c17 deficiency.2 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.
Y 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.

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

„ Females with P450c17 deficiency

Y Affected 46,XX females have normal external and internal female differentiation; newborn females appear normal.
Y Adolescent and older women may exhibit sexual infantilism and little or no pubic or axillary hair.
Y The first described female patient presented with hypertension, hypokalemia, no breast development, primary amenorrhea, and lack of
pubic and axillary hair.
Y Internally, patients have a small prepubertal uterus and may have multicystic ovaries, presumably from gonadotropic stimulation.
„ Males with P450c17 deficiency
Y Genitals of affected males vary from phenotypic female to ambiguous male genitalia.
Y Gynecomastia has been reported in a male patient with ambiguous genitalia.
Y The patient may present as an otherwise normal-appearing female with lack of secondary sexual characteristics. Closer examination
reveals the vagina to be a blind pouch, and the patient lacks internal genitalia.
Y Testes may be undescended or located in the inguinal canal.
Y Histology of the testes reveals atopic tubules, Sertoli cells, and Leydig cell hyperplasia.
Y Although rarely diagnosed in younger children, an abdominal hernia or inguinal mass in an otherwise normal-appearing female infant or
child, especially if combined with hypertension, suggests a diagnosis of 17-hydroxylase 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.6,7,8

Causes
17-hydroxylase deficiency is inherited as an autosomal recessive trait involving the J
 gene. A common mutation within the J
 gene was identified in 2
Canadian patients from 2 apparently unrelated Mennonite families in Canada. This mutation was also found in 6 Mennonite families in the
Netherlands.14 Congenital adrenal hyperplasia associated with P450 oxidoreductase (POR) deficiency is due to inactivating
 gene mutations.5