Clinical evaluation Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens
in utero.
CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants (46XX). Less severely affected females may present with early
pubarche. Young women may present with symptoms of
polycystic ovarian syndrome (
oligomenorrhea, polycystic ovaries,
hirsutism). Males with classic CAH generally have no signs of CAH at birth. Some may present with
hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone, and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of
aldosterone deficiency. Boys with salt-wasting disease present early with symptoms of
hyponatremia and
hypovolemia. Boys with non-salt-wasting disease present later with signs of virilization. and females generally have no signs or symptoms at birth. CAH can be diagnosed through evaluation of the
ACTH stimulation test.
Laboratory studies Genetic analysis can be helpful to confirm a diagnosis of CAH, but it is not necessary if classic clinical and laboratory findings are present. In classic 21-hydroxylase deficiency, laboratory studies will show: :*
Hypoglycemia (due to hypocortisolism) - One of cortisol's many functions is to increase blood glucose levels. This occurs via a combination of several mechanisms, including (a) the stimulation of gluconeogesis (i.e. the creation of new glucose) in the liver, (b) the promotion of glycogenolysis (i.e. the breakdown of glycogen into glucose), and (c) the prevention of glucose leaving the bloodstream via the downregulation of GLUT-4 receptors (which normally promote movement of glucose from the bloodstream into adipose and muscle tissues). Therefore, when cortisol is deficient, these processes (effectively) occur in the reverse direction. Although there are compensatory mechanisms that mitigate the impact of hypocortisolism, they are limited in their extent and the net effect is still hypoglycemia. :*
Hyponatremia (due to hypoaldosteronism) - Aldosterone is the end product of the renin-angiotensin-aldosterone system that regulates blood pressure via blood pressure surveillance in the Kidney Juxtaglomerular apparatus. Aldosterone normally functions to increase sodium retention (which brings water as well) in exchange for potassium. Thus, lack of aldosterone causes hyperkalemia and hyponatremia. In fact, this is a distinguishing point from 11-hydroxylase deficiency, in which one of the increased products is 11-deoxycorticosterone that has weak mineralocorticoid activity. In 11-hydroxylase deficiency, 11-deoxycorticosterone is produced in such excess that it acts to retain sodium at the expense of potassium. It is this reason that patients with 11-hydroxylase deficiency do not show salt wasting (although sometimes they do in infancy), and instead have hypertension/water retention and sometimes hypokalemia. :*
Hyperkalemia (due to hypoaldosteronism) :* Elevated
17α-hydroxyprogesterone Classic 21-hydroxylase deficiency typically causes 17α-hydroxyprogesterone blood levels >242 nmol/L. (For comparison, a full-term infant at three days of age should have <3 nmol/L. Many neonatal screening programs have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without CAH.) Salt-wasting patients tend to have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a
corticotropin stimulation test.
Classification Cortisol is an adrenal steroid hormone required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of
ACTH, because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH. This increased ACTH stimulation induces overgrowth (
hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e. present at birth). : The enzymes affected in CAH are represented by one red and four green bars on the top half of the diagram (for example, "21α-hydroxylase" is visible near the top center. "17α-hydroxylase" and "17,20 lyase" are carried out by a single enzyme). Depending upon which enzyme is unavailable, production of
androgens (lower left) or
mineralocorticoids (upper right) is reduced. This, in turn, can lead to increased production of other molecules, due to a buildup of precursors. Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone,
androgens such as
testosterone, and
estrogens such as
estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids. Since the 1960s, most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be
cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases, a single enzyme mediated in more than one reaction. Variation in different tissues and mammalian species also was found. In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition.) CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges, as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency. ==Screening==