NCAH is encountered with relatively high frequency (1 - 6%) among adolescent and adult patients with hyperandrogenism. This incidence may vary from one geographic area to another, as reported for classical 21-OHD, because of ethnic and racial clusters.
The 21-hydroxylase deficiency is responsible for an oversecretion of 17-HP and other steroids that are upstream this enzymatic step. Mutations resulting in NCAH reduce the activity of 21-hydroxylase to 20 - 50%. This is not sufficient to impair the physiologically needed cortisol production, providing that the amount of precursor required is much greater than normal, thus compensating for the lower enzyme efficiency. The alteration in the enzyme kinetic is therefore sufficient to explain the excessive accumulation of 21-OH precursors, mainly progesterone and 17-HP, in the presence of a normal stimulation by ACTH. This excess is partly converted to androgens, resulting in adrenal hyperandrogenism. Therefore, NCAH is essentially a hyperandrogenic disorder, without overt abnormality in the gluco- and mineralocorticosteroid pathways.
To understand why NCAH expresses itself only during or after puberty, it must be recalled that the steroidogenic changes accompanying adrenarche result in an increased 17,20-lyase and a decreased 3β-hydroxysteroid dehydrogenase-isomerase activity, thus increasing the adrenal output of Δ5 androgens. Such a phenomenon acting while 21-hydroxylase is partly deficient could be the physiological trigger of hyperandrogenism in NCAH.
Before the age of 7 - 8 years, NCAH may mimic an idiopathic premature pubarche or, more rarely, a virilizing ovarian or adrenal tumor, especially when there are symptoms of precocious pseudo-puberty, such as accelerated height velocity and clitoromegaly. In the first series, the prevalence of NCAH compared to the other causes of premature pubarche was debated, varying from 0% to more than 20%, mainly because of differences in diagnostic criteria. More recently, it has been estimated at 6 - 8%, justifying the measurement of the 17-HP morning level in this situation.
Numerous studies have shown that adolescent or adult women with NCAH are seldom more virilized than other women with ovarian causes of hyperandrogenism and that no symptom of hyperandrogenism is specific for NCAH.
Furthermore, NCAH may also be detected in individuals having mild symptoms such as acne. Therefore, the clinical presentation cannot be used for the diagnosis of NCAH. Clitoromegaly, male habitus and temporal baldness are infrequent findings, unless the patient suffers from undiagnosed simple virilizing CAH. Recently, it has been suggested from a multicenter study including 220 patients that NCAH is a progressive disorder since the prevalence of hirsutism increases with the patient’s age.
The diagnosis of NCAH should be considered in those patients selected from a basal 17-HP >2ng/ml (see above) and in whom the post-stimulation 17-HP level exceeds 10 ng/ml (30.3 nmol/l). Between this threshold and the upper normal limit which is about 3 ng/ml in most studies, there is the range of heterozygotes who are unaffected carriers and that of patients with functional ovarian and/or adrenal hyperandrogenism. The former may have a post-stimulation 17-HP level as high as 15 ng/ml, but in any case their basal 17-HP level exceeds 2ng/ml.
Once the biochemical diagnosis has been obtained, genotypes from adolescent patients with NCAH should be obtained as early as possible, in order to be ready for genetic counseling when they desire a pregnancy.
Revision date: July 4, 2011
Last revised: by Sebastian Scheller, MD, ScD