C-17 Hydroxylase Deficiency Workup

Updated: Dec 16, 2014
  • Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD  more...
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Workup

Laboratory Studies

A diagnosis may be established by measuring precursor-to-product ratios during an ACTH stimulation test.

  • The 17-deoxy steroids, as well as progesterone, corticosterone, and DOC, rise to 5-10 times their normal levels following ACTH stimulation. The aldosterone levels in most cases are low due to the renin suppression induced by the elevated levels of DOC and other precursor mineralocorticoids.
  • Elevated progesterone, corticosterone, and DOC levels in the setting of a virtual absence of 17-hydroxyprogesterone, estrogens, and androgens are characteristic of the syndrome.
  • Corticosterone typically is 50- to 100-fold higher than the reference range.
  • Most patients have DOC levels greater than 100 ng/dL (normal levels being 2-20 ng/dL).
  • The majority of patients (80-90%) present with hypokalemic metabolic alkalosis.
  • Patients have elevated levels of 18-hydroxycorticosterone and 18-hydroxydeoxycorticosterone.
  • Follicle-stimulating hormone and luteinizing hormone levels are markedly elevated, while ACTH levels are marginally elevated.
  • Patients with isolated 17,20-lyase deficiency may have normal 17-hydroxyprogesterone, cortisol, and 11-deoxycortisol levels, with low levels of androgens and estrogens, testosterone, androstenedione, DHEA, DHEA sulfate (DHEA-S), and estradiol. These findings are exaggerated with ACTH and human chorionic gonadotrophin stimulation. Patients also may have normal DOC levels.
  • Biochemical testing may detect heterozygosity in family members of patients with 17-hydroxylase deficiency.
    • Corticosterone and 18-hydroxycorticosterone levels, as well as the 18-hydroxycorticosterone – to – aldosterone ratio, are elevated following ACTH stimulation.
    • Heterozygotes may have exaggerated responses to ACTH stimulation. [18]
    • The ratio of urinary metabolites of corticosterone to those of cortisol is low.

Molecular genetics is highly sensitive but currently is available only in research laboratory settings.

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Imaging Studies

The diagnosis of this condition is not made by radiologic findings. However, being aware of potential radiologic findings that may have been obtained in the course of a workup for hypogonadism or ambiguous genitalia is worthwhile. [19]

  • Abdominal computed tomography (CT) scanning or magnetic resonance imaging (MRI) may reveal bilateral thickening of the limbs of the adrenal.
  • Occasionally, the adrenals may have a multinodular appearance, particularly in adult patients.
  • NP-59 Iodo cholesterol scans are not necessary or performed routinely. Findings are consistent with the adrenocortical hyperplasia associated with congenital adrenal hyperplasia (ie, bilateral radioisotope uptake).

Pelvic ultrasonography reveals a lack of m ü llerian structures in 46,XY patients and demonstrates normal, but underdeveloped, m ü llerian structures in 46,XX patients. The gonads may be intra-abdominal or in the inguinal canal in 46,XY patients.

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Other Tests

In patients presenting with primary amenorrhea and sexual infantilism, karyotyping to determine the genetic sex of the patient is important. Even in genetic XY patients who have been hitherto raised as females, recognition of the genetic sex is critical, because the undescended testes in these patients invariably need to be removed surgically, given their potential for malignant degeneration over time. The associated increased risk for the development of intratubular germ cell tumors is estimated to be 40-100 times more common in the setting of cryptorchidism.

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Histologic Findings

A description of the histologic findings in patients with 17-hydroxylase deficiency is as sparse as the total number reported cases.

Typically, the adrenal glands are hyperplastic, enlarged, and show diffuse nodular hyperplasia, diffuse cortical hyperplasia, or adenomatous hyperplasia. The adrenal cortex, predominantly the zona fasciculata and the reticularis, is the area involved in the hyperplasia. The zona glomerulosa reportedly is normal histologically. The component cells involved in the hyperplasia typically are clear cells, with sporadic myelolipomatous tissue noted in several cases. A few cases have been reported in which the hyperplasia is associated with coexisting adenomas.

In one case, pituitary gland examination showed evidence of enlargement found to be secondary to ACTH basophil cell hyperplasia.

The ovarian pathologic findings are variable. Multiple ovarian cysts have been described in adult patients, and the ovaries ultimately have a polycystic appearance (probably as a result of chronic gonadotrophin stimulation). The ovaries typically show fibrous stromal cells without hyperplasia, few ova, and few follicles. However, most of the follicles are atretic, with a few small graafian follicles.

The testes usually are small, with atrophic seminiferous tubules and little evidence of spermatogenesis. Associated secondary Leydig cell hyperplasia also is present. The testes often are ectopically located. As is true for ectopic testes and in patients with other forms of steroid biosynthetic defects, patients with 17-hydroxylase deficiency require gonadectomy to prevent malignant degeneration of their intra-abdominal testes.

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