17-Hydroxylase Deficiency Syndrome Clinical Presentation

  • Author: J Paul Frindik, MD, FACE; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: May 10, 2012
 

History

In general, patients with 17-hydroxylase (17-OH) deficiency have no history of adrenal insufficiency nor adrenal crisis, presumably due to elevated levels of corticosterone (see Mortality/Morbidity). Patients may have a history of hypertension; alternatively, hypertension may be the presenting complaint. Both the age of onset and degree of severity of hypertension seem to vary between patients.[2]

  • 46,XX karyotype with P450c17 deficiency
    • Virilization and development of ambiguous genitalia do not occur in 46,XX patients with 17-hydroxylase deficiency.
    • Unless hypertension is discovered, females may have no historical complaints or findings until puberty.
    • The ovaries are unable to secrete either androgens or estrogens necessary for sexual maturation, and the adrenal glands cannot secrete androgens necessary for pubic and axillary hair growth. Consequently, adolescent or older females present with complaints of delayed puberty,[2] ) primary amenorrhea,[19] , and lack of secondary sexual characteristics.
  • 46,XY karyotype with P450c17 deficiency
    • Under-masculinization always occurs in 46,XY individuals with complete P450c17 deficiency.[2] The genitals of such patients vary from phenotypic female to ambiguous male genitalia. Males with phenotypic female genitalia may go undetected until puberty, at which time they present with complaints similar to those of 46,XX patients.
    • The diagnosis may be suspected in an apparent female infant or young child with a history of an abdominal hernia, inguinal mass, or otherwise unexplained hypertension.
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Physical

Mildly to severely elevated blood pressure may be the primary finding in patients with 17-hydroxlase deficiency syndrome.

  • 46,XX karyotype with P450c17 deficiency
    • Affected 46,XX individuals have phenotypic female normal external and internal female differentiation.
    • Adolescent and older women may exhibit sexual infantilism and little or no pubic or axillary hair.
    • The first described female patient presented with hypertension, hypokalemia, no breast development, primary amenorrhea, and lack of pubic and axillary hair.
    • Internally, patients have a small prepubertal uterus and may have multicystic ovaries, presumably from gonadotropic stimulation.
  • 46,XY karyotype with P450c17 deficiency
    • Genitals of affected 46,XY individuals vary from phenotypic female to ambiguous male genitalia.
    • Gynecomastia has been reported in a male patient with ambiguous genitalia.
    • The patient may present as an otherwise phenotypic normal female; however secondary sexual characteristics are missing. Closer physical examination reveals the vagina to be a blind pouch, and the patient lacks internal genitalia.
    • Testes may be undescended or located in the inguinal canal.
    • Histology of the testes reveals atopic tubules, Sertoli cells, and Leydig cell hyperplasia.
    • Although rarely diagnosed in younger children, an abdominal hernia or inguinal mass in a phenotypic female infant or child, especially if combined with hypertension, suggests a diagnosis of 17-hydroxylase deficiency.

Patients with P450 oxidoreductase (POR) deficiency have varying degrees of adrenal insufficiency and genital anomalies. Skeletal malformations, including craniosynostosis, radio-ulnar synostosis, midface hypoplasia, and bowed femurs (Antley-Bixler syndrome), may be caused by fibroblast growth factor 2 receptor mutations, but have also been reported in patients with POR deficiency. Genital anomalies are found in both male and female patients with POR deficiency. Affected males may be ambiguous as would be expected from the low levels of sex steroids. However, affected females with POR can actually present with severe virilization. Virilization in such affected 46 XX females may be due to an alternative androgen pathway involving dihydrotestosterone synthesis, but the exact mechanism remains incompletely explained.[9, 10, 11]

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Causes

17-hydroxylase deficiency is inherited as an autosomal recessive trait involving the CYP17 gene. A common mutation within the CYP17 gene was identified in 2 Canadian patients from 2 apparently unrelated Mennonite families in Canada. This mutation was also found in 6 Mennonite families in the Netherlands.[20] Congenital adrenal hyperplasia associated with P450 oxidoreductase (POR) deficiency is due to inactivating POR gene mutations.[5]

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Contributor Information and Disclosures
Author

J Paul Frindik, MD, FACE  Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences

J Paul Frindik, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists

Disclosure: Nothing to disclose.

Specialty Editor Board

Erawati V Bawle, MD, FAAP, FACMG  Retired Professor, Department of Pediatrics, Wayne State University School of Medicine

Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American College of Medical Genetics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD  Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References

  1. Auchus RJ, Gupta MK. Towards a unifying mechanism for CYP17 mutations that cause isolated 17,20-lyasedeficiency. Endocr Res. Nov 2002;28(4):443-7. [Medline].

  2. Rosa S, Duff C, Meyer M, et al. P450c17 deficiency: clinical and molecular characterization of six patients. J Clin Endocrinol Metab. Mar 2007;92(3):1000-7. [Medline].

  3. Tian Q, Zhang Y, Lu Z. Partial 17alpha-hydroxylase/17,20-lyase deficiency-clinical report of five Chinese 46,XX cases. Gynecol Endocrinol. Jul 2008;24(7):362-7. [Medline].

  4. Bhangoo A, Aisenberg J, Chartoffe A, et al. Novel mutation in cytochrome P450c17 causes complete combined 17alpha-hydroxylase/17,20-lyase deficiency. J Pediatr Endocrinol Metab. Feb 2008;21(2):185-90. [Medline].

  5. Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. Apr 2009;23(2):181-92. [Medline].

  6. Bao X, Ding H, Xu Y, Cui G, He Y, Yu X, et al. Prevalence of common mutations in the CYP17A1 gene in Chinese Han population. Clin Chim Acta. Jun 11 2011;412(13-14):1240-3. [Medline].

  7. Tian Q, Yao F, Zhang Y, Tseng H, Lang J. Molecular study of five Chinese patients with 46XX partial 17a-hydroxylase/17,20-lyase deficiency. Gynecol Endocrinol. Mar 2012;28(3):234-8. [Medline].

  8. Costa-Santos M, Kater CE, Auchus RJ, Brazilian Congenital Adrenal Hyperplasia Multicenter Study Group. Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab. Jan 2004;89(1):49-60. [Medline]. [Full Text].

  9. Fluck CE, Pandey AV, Huang N, et al. P450 oxidoreductase deficiency - a new form of congenital adrenal hyperplasia. Endocr Dev. 2008;13:67-81. [Medline].

  10. Scott RR, Miller WL. Genetic and clinical features of p450 oxidoreductase deficiency. Horm Res. 2008;69(5):266-75. [Medline].

  11. Arlt W. P450 oxidoreductase deficiency and Antley-Bixler syndrome. Rev Endocr Metab Disord. Dec 2007;8(4):301-7. [Medline].

  12. Fukami M, Horikawa R, Nagai T, Tanaka T, Naiki Y, Sato N, et al. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab. Jan 2005;90(1):414-26. [Medline].

  13. Aydin Z, Ozturk S, Gursu M, Uzun S, Karadag S, Kazancioglu R. Male pseudohermaphroditism as a cause of secondary hypertension: a case report. Endocrine. Aug 2010;38(1):100-3. [Medline].

  14. Kandemir N, Yordam N. Congenital adrenal hyperplasia in Turkey: a review of 273 patients. Acta Paediatr. Jan 1997;86(1):22-5. [Medline].

  15. Rosado A, Alegre M, Colon G. [Male pseudohermaphroditism caused by enzymatic deficiency of 17-alpha- hydroxylase. 1st case reported in Puerto Rico]. Bol Asoc Med P R. Oct-Dec 1997;89(10-12):197-9. [Medline].

  16. Hershkovitz E, Parvari R, Wudy SA, et al. Homozygous Mutation G539R in the Gene for P450 Oxidoreductase in a Family Previously Diagnosed as Having 17,20-Lyase Deficiency. J Clin Endocrinol Metab. Sep 2008;93(9):3584-8. [Medline].

  17. Monig H, Sippell W. Congenital adrenal hyperplasia in adulthood: do men need to continue treatment?. Horm Res. 2005;64 Suppl 2:71-3. [Medline].

  18. Ross RJ, Rostami-Hodjegan A. Timing and type of glucocorticoid replacement in adult congenital adrenal hyperplasia. Horm Res. 2005;64 Suppl 2:67-70. [Medline].

  19. Philip J, Anjali N, Thomas S, et al. 17-Alpha hydroxylase deficiency: an unusual cause of secondary amenorrhoea. Aust N Z J Obstet Gynaecol. Oct 2004;44(5):477-8. [Medline].

  20. Imai T, Yanase T, Waterman MR, et al. Canadian Mennonites and individuals residing in the Friesland region of The Netherlands share the same molecular basis of 17 alpha-hydroxylase deficiency. Hum Genet. Apr 1992;89(1):95-6. [Medline].

  21. Biglieri EG, Herron MA, Brust N. 17-hydroxylation deficiency in man. J Clin Invest. Dec 1966;45(12):1946-54. [Medline]. [Full Text].

  22. Ducharme JR, Forest MG. Normal pubertal development. In: Pediatric Endocrinology: Physiology, Pathophysiology & Clinical Aspects. 2nd ed. 1993:372-86.

  23. Forest MG, Lecornu M, de Peretti E. Familial male pseudohermaphroditism due to 17-20-desmolase deficiency. I. In vivo endocrine studies. J Clin Endocrinol Metab. May 1980;50(5):826-33. [Medline].

  24. Grumbach MM, Conte FA. Disorders of sex differentiation. In: Williams Textbook of Endocrinology. 8th ed. 1992:853-951.

  25. Kater CE, Biglieri EG. Disorders of steroid 17 alpha-hydroxylase deficiency. Endocrinol Metab Clin North Am. Jun 1994;23(2):341-57. [Medline].

  26. Orth DN, Kovacs WJ, Debold CR. The adrenal cortex. In: Williams Textbook of Endocrinology. 8th ed. 1992:489-619.

 
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Normal adrenal steroid biosynthesis results in 3 products: mineralocorticoids (aldosterone), glucocorticoids (cortisol), and androgens (androstenedione). Cortisol production is regulated by feedback with adrenocorticotropic hormone (ACTH). ACTH stimulates the enzyme P-450scc (20,22 desmolase), with subsequently increased production of all adrenal steroids.
Representation of typical congenital adrenal hyperplasia (CAH). This example shows a deficiency in both the mineralocorticoid and glucocorticoid pathways. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion causes overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. The example depicts a deficiency of 21-hydroxylase, resulting in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.
C-17α-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog). Absence of C-17α-hydroxylase impairs all sex steroid and cortisol production. Low levels of cortisol result in increased adrenocorticotropic hormone (ACTH) stimulation of steroids prior to the 17-hydroxylase step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone.
Graphic illustration of deficiency. Absence of C-17α-hydroxylase impairs all sex steroid and cortisol production.
 
 
 
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