eMedicine Specialties > Endocrinology > Adrenal Gland

C-17 Hydroxylase Deficiency: Differential Diagnoses & Workup

Author: Gabriel I Uwaifo, MBBS, Clinical and Research Attending, Assistant Professor of Medicine and Endocrinology, MedStar Clinical Research Center, MedStar Research Institute and Washington Hospital Center
Contributor Information and Disclosures

Updated: Jan 17, 2009

Differential Diagnoses

5-Alpha-Reductase Deficiency
Hypokalemia
Adrenal Adenoma
Hypomagnesemia
Amenorrhea, Primary
Hyporeninemic Hypoaldosteronism
C-11 Hydroxylase Deficiency
Infertility
Conn Syndrome
Infertility, Male
Cushing Syndrome
Metabolic Alkalosis
Encephalopathy, Hypertensive
Osteoporosis
Hyperaldosteronism, Primary
Ovarian Failure

Other Problems to Be Considered

3-beta hydroxylase steroid dehydrogenase deficiency
Androgen resistance syndromes
Lipoid congenital adrenal hyperplasia
Pure and/or mixed gonadal dysgenesis
Hypertension due to 11-beta hydroxylase deficiency
Hypertension due to primary hyperaldosteronism
Hypertension due to glucocorticoid remediable aldosteronism
Hypothalamic pituitary amenorrhea
Primary ovarian failure
Premature ovarian failure
Testicular feminization syndrome
Delayed puberty
Hypogonadotropic hypogonadism
Ambiguous genitalia

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.14
    • 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.

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.
    • 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.

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.

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.

More on C-17 Hydroxylase Deficiency

Overview: C-17 Hydroxylase Deficiency
Differential Diagnoses & Workup: C-17 Hydroxylase Deficiency
Treatment & Medication: C-17 Hydroxylase Deficiency
Follow-up: C-17 Hydroxylase Deficiency
Multimedia: C-17 Hydroxylase Deficiency
References
Further Reading
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References

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  3. Arlt W, Walker EA, Draper N, et al. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet. Jun 26 2004;363(9427):2128-35. [Medline].

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Further Reading

Related eMedicine topics:
 17-Hydroxylase Deficiency Syndrome
C-11 Hydroxylase Deficiency
Congenital Adrenal Hyperplasia
Hypertension [Nephrology]
Hypertension [Pediatrics: Cardiac Disease and Critical Care Medicine]
Hypokalemia [Emergency Medicine]
Hypokalemia [Nephrology]
Hypokalemia [Pediatrics: Cardiac Disease and Critical Care Medicine]

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Keywords

C-17 hydroxylase deficiency, hypertension, estrogen, cortisol, adrenal, androgen, hypokalemia, aldosterone, ACTH, renin, adrenal glands, adrenal hyperplasia, congenital adrenal hyperplasia, androgens, congenital hyperplasia, glucocorticoid, glucocorticoids, mineralocorticoid, estrogens, adrenocorticotropic hormone, corticosterone, pseudohermaphroditism, CAH, deoxycorticosterone, sexual infantilism, CYP17, gonadal steroidogenesis, 17-alpha hydroxylase deficiency

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Contributor Information and Disclosures

Author

Gabriel I Uwaifo, MBBS, Clinical and Research Attending, Assistant Professor of Medicine and Endocrinology, MedStar Clinical Research Center, MedStar Research Institute and Washington Hospital Center
Gabriel I Uwaifo, MBBS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Society of Hypertension, and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Ghassem Pourmotabbed, MD†, Former Associate Professor, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Tennessee School of Medicine and Health Science Center
Ghassem Pourmotabbed, MD† is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

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