The steroidogenic
enzyme 21-hydroxylase is necessary for the synthesis of both
glucocorticoids and
mineralocorticoids.
21-hydroxylase is a
cytochrome P-450 enzyme and is encoded by the gene CYP21A2. Here we report a 68-year-old phenotypically 'male' but genetically female patient with
21-hydroxylase deficiency (21OHD) and the concomitant virilizing
adrenocortical carcinoma. This patient grew up as a male and has not encountered any episodes of
adrenal insufficiency without
glucocorticoid replacement in his lifetime. A chromosome test at admission, however, identified the 46, XX karyotype, and serum
17-hydroxyprogesterone and urine
pregnanetriolone and 11β-hydroxyandrostendione were all elevated, consistent with 21OHD. Moreover, serum
testosterone was 1.90 ng/ml, much higher than the female standard levels, and serum
cortisol was 5.7 µg/ml, slightly lower than standard levels. Genetic analysis identified the patient as a heterozygote of the two pathogenic mutations in the CYP21A2 gene: IVS2-13C(A)>G and R356W. Magnetic resonance imaging (MRI) revealed the presence of left adrenal
tumor measuring 6 cm, which was subsequently diagnosed as
adrenocortical carcinoma based on the criteria of Weiss. Immunohistochemical analysis of the
tumor specimens revealed the expression of various
enzymes involved in
testosterone production, including 3β-hydroxysteroid
dehydrogenase, 17α-
hydroxylase/
17,20-lyase, and 17β-hydroxysteroid
dehydrogenase. Importantly, the expression of immunoreactive
21-hydroxylase was detected in these
tumor cells. The levels of adrenal
tumor-derived
steroid metabolites were all markedly decreased following the surgery. This is the first report on a virilized 21OHD patient associated with the adrenocortical
tumor that produces
testosterone. Moreover, the concomitant adrenocortical
tumor may ameliorate adrenocortical insufficiency by producing
cortisol.