A 68-Year-Old Phenotypically Male Patient with 21-Hydroxylase Deficiency and Concomitant Adrenocortical Neoplasm Producing Testosterone and Cortisol

Abstract

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.

Prevalence and Characteristics of Adrenal Tumors and Myelolipomas in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis

“…These cases were not included in the analysis due to low numbers; nine had 17α-hydroxylase deficiency (59,(64)(65)(66)(67)(68)(69) and one 11β-dehydrogenase deficiency (70). For the same reason four case reports with adrenal cortical cancer and 21OHD also were excluded (71)(72)(73)(74). A fifth case with cortical cancer and CAH was published autumn and was a mixed tumor with myelolipoma and included in Table 3 (63).…”

Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome

“…In some of these cases, the diagnosis of CAH, both classic and NCAH, was made on the urinary steroid profile sampled in the work-up of suspected adrenocortical cancer [24,29,185]. Even though adrenocortical cancer is rare in CAH, there are occasional case reports on previously both diagnosed and undiagnosed classic CAH [162,186] and on undiagnosed NCAH [187,188]. Thus, when tumors are found, a conventional evaluation should be performed to exclude other types of tumors that demand treatment.…”

Late onset adrenal insufficiency after adrenalectomy due to latent nonclassical 21-hydroxylase deficiency

“…[ 1 , 2 ] In addition, adrenalectomy is not performed on the background of 21-OHD because of the risk of future adrenal crisis, unless malignancy could not be excluded when adrenalectomy is occasionally performed. [ 5 , 6 ] Although adrenal insufficiency usually occurs immediately after adrenalectomy, [ 7 ] this is not always the case. Therefore, the strategy of handling adrenal incidentaloma in patients with 21-OHD still remains to be unified.…”