Deficiency of 21-hydroxylase occurs in three forms: 1) simple virilizing, 2) salt-wasting, and 3) nonclassical. The simple virilizing and salt-wasting forms of 21-hydroxylase deficiency are characterized by excess adrenal Deficiency of 21-hydroxylase occurs in three forms: 1) simple virilizing, 2) salt-wasting, and 3) nonclassical. The simple virilizing and salt-wasting forms of 21-hydroxylase deficiency are characterized by excess adrenal androgen biosynthesis in utero, which causes prenatal virilization of the genetic female and postnatal virilization of both boys and girls. Biochemically, the conversion of 17-hydroxyprogesterone (17-OHP), the main substrate of the 21-hydroxylase enzyme, to 11-deoxycortisol in the pathway of cortisol synthesis is impaired (Figure 1). Baseline and ACTH stimulated serum levels of cortisol precursors may be extremely elevated in untreated patients, principally, 17-OHP. The 21-hydroxylase enzyme defect can also impair the conversion of progesterone to 11-deoxycorticosterone (DOC) in the pathway of aldosterone synthesis, as occurs in the salt-wasting form. Aldosterone production is not sufficient for sodium reabsorption by the distal renal tubules causing low serum sodium, high serum potassium, in addition to increased levels of adrenal androgen and cortisol precursors seen in simple virilizers. In salt-wasting CAH, both newborn boys and girls are subject to early, life-threatening, salt-wasting crises within the first few weeks of life.
Hormonal diagnosis of 21-hydroxylase deficiency is established by comparison of baseline and ACTH stimulated serum levels of 17-OHP. (2) A nomogram provides hormonal standards for assignment of the 21-hydroxylase phenotype (Figure 2). Because of the diurnal variation in l7-OHP, an early morning serum concentration of l7-OHP may be useful as a screening test for genotyping 21-OHD. ACTH stimulation, however, remains the most definitive hormonal diagnostic test. An ACTH stimulation test should not be performed during the initial 24 hours of life as samples from this period are typically elevated in all infants and may yield false-positive results.
Figure 2. Nomogram for hormonal diagnosis of 21-hydroxylase deficiency relating baseline to ACTH-stimulated serum concentrations of 17-OHP. Scales are logarithmic. A regression line for all data points is shown.
Nonclassical CAH, sometimes called late-onset, occurs when there is only a mild deficiency of enzyme 21-hydroxylase. These patients do not waste salt, and females are not virilized at birth. Nonclassical 21-hydroxylase deficiency may present at any age postnatally, with patients exhibiting moderately high androgens and stimulated levels of 17-OHP. (3)
The various clinical and biochemical features associated with the different forms of 21-hydroxylase deficiency are presented in Table 1.
Prenatal Virilization
In utero virilization occurs in genetic females (46, XX) affected with simple virilizing or salt-wasting 21-hydroxylase deficiency. Excessive adrenal androgens masculinize the external genitalia (female pseudohermaphroditism), so that an affected newborn female may present with varying degrees of virilization including a urogenital sinus, scrotalization of the labia majora, labial fusion, or clitoromegaly. In rare cases, the masculinization is so profound that the urethra is penile. (4) A five stage classification by Prader (5) is used to represent different degrees of virilization (Figure 3), where on a scale of 1 to 5 (I-V) the genitalia can be scored from slightly virilized (e.g., mildly enlarged clitoris) to that resembling a male with a penile urethra. Most females with 21-hydroxylase deficiency are born with Prader IV genitalia. As females with CAH have a 46, XX karyotype and do not have testes, anti-müllerian hormone (AMH) is not secreted, and müllerian ducts develop normally into a uterus and fallopian tubes. Thus, females with 21-hydroxylase deficiency have the potential for fertility.
Figure 3. Diagrams representing five degrees of virilization affecting the urogenital sinus and external genitalia in females. (5)
It is not possible to distinguish between simple virilizing classical 21-OHD and salt-wasting classical 21-OHD based solely on the degree of virilization of an affected female at birth. In pregnancies at risk of a female child affected with congenital adrenal hyperplasia, successful suppression of fetal adrenal androgen production has resulted by giving the mother dexamethasone, a glucocorticoid able to cross the placental barrier. (6)