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17-Hydroxylase Deficiency Syndrome
Article Last Updated: Jun 1, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: J Paul Frindik, MD, FACE, Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences
J Paul Frindik is a member of the following medical societies: American Association of Clinical Endocrinologists
Editors: Erawati V Bawle, MD, FAAP, FACMG, Director, Division of Genetic and Metabolic Disorders, Department of Pediatrics, Children's Hospital of Michigan; Professor (Clinician-Educator), Wayne State University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School
Author and Editor Disclosure
Synonyms and related keywords:
17-hydroxylase deficiency, P-450c17 hydroxylase deficiency, 17-alpha-hydroxylase deficiency, 17-OH, 17-OH deficiency
Background
17-hydroxylase (17-OH) deficiency syndrome is a rare genetic disorder of steroid biosynthesis causing decreased production of glucocorticoids and sex steroids and increased synthesis of mineralocorticoid precursors. Reduced or absent levels of both gonadal and adrenal sex hormones result in sexual infantilism in 46,XX females and ambiguous genitalia in 46, XY males. Excessive mineralocorticoid activity produces varying degrees of hypertension and hypokalemia. Patients usually are diagnosed with this condition during an evaluation of delayed puberty, absent secondary sexual characteristics or primary amenorrhea.
Pathophysiology
Anatomically, the adrenal gland can be divided into 3 zones:
- Zona glomerulosa, which produces predominately mineralocorticoid
- Zona fasciculata, which produces predominately glucocorticoid
- Zona reticularis, which produces predominately androgens
For convenience, think of the zona glomerulosa as the first endocrine organ and the zonae fasciculata and reticularis collectively as a second separate endocrine organ, as distinguished by distinct control systems. Aldosterone (mineralocorticoid) synthesis and secretion is regulated via the renin-angiotensin system, which is responsive to the electrolyte balance state and plasma volume. Aldosterone secretion also is stimulated directly by high serum potassium concentrations. In contrast, cortisol synthesis and secretion is regulated by adrenocorticotropic hormone (ACTH), which stimulates the enzyme P-450scc (20, 22 desmolase) with subsequent increased production of all adrenal steroids in both the zona fasciculata and zona reticularis (see Image 1). Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of adrenal steroid biosynthesis in which one of the enzymes necessary for cortisol production has deficient activity. Decreased serum cortisol levels stimulate ACTH release via negative feedback. The adrenal glands undergo hypertrophy, apparently due to ACTH-stimulated production of insulinlike growth factor-2 (IGF-2). Increased ACTH secretion also results in overproduction of both the adrenal steroids preceding the missing enzyme and those not requiring the missing enzyme (ie, build-up of compounds both before the block and "sideways" from the block; see Image 2). Treatment with exogenous glucocorticoid decreases ACTH secretion and subsequent suppression of overproduced steroids. P-450c17, an enzyme complex present in Leydig cells, ovarian follicles, and the adrenal zonae fasciculata and reticularis, catalyzes both 17-OH and 17,20 lyase activity. P-450c17 is the product of the CYP17 gene; the following are defects attributed to mutations of this gene:
- Isolated 17-OH deficiency
- Isolated 17,20 lyase deficiency
- Combination of 17-OH and 17,20 lyase deficiency
C-17alpha-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog); see Image 3. Absence of this enzyme thus impairs all sex steroid and cortisol production (see Image 4). Low levels of cortisol result in increased ACTH stimulation of steroids prior to the 17-OH step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone (compound B). Hypogonadism occurs as a result of deficient sex steroid production. DOC mineralocorticoid activity causes sodium retention, plasma volume expansion, hypertension, hypokalemia, and decreased renin and aldosterone levels in most untreated patients with 17-OH deficiency. In order to better define the molecular basis of 17-OH deficiency, genetic analysis was performed on 19 families with 17-OH deficiency (Costa-Santos, 2004). Seven different CYP17 mutations were found among 24 subjects. However, 2 mutations accounted for most cases: W406R (50%) and R362C (32%). Phenotypic features varied among the subjects and did not correlate with the CYP17 genotype, suggesting other factors besides the CYP17 genotype influence the phenotypic presentation.
Frequency
International
Between 80-90% of individuals with CAH have 21-hydroxylase deficiency. The incidence of classic 21-hydroxylase deficiency varies from 1 in 5000-15,000 live births in white populations to 1 in 300-700 in the Alaskan Yupik population. The second most common type of CAH, 11-beta-hydroxylase deficiency, has an incidence of about 1 in 100,000; 17-OH deficiency probably is even more rare. Some estimate the occurrence of 17-OH deficiency at approximately 1 case per 50,000 individuals.
17-OH deficiency occurs worldwide. As of 1997, approximately 120 individuals had been reported with severe, confirmed 17-OH deficiency. Most cases were isolated or occurred in small clusters. Examples include Turkey, where the reported incidence was 1 of 273 patients with CAH over a 25-year period, Brazil with 16 cases over a 10-year period, and Puerto Rico with 1 reported case.
Mortality/Morbidity
- Although cortisol-deficient, patients do not have adrenal insufficiency or experience adrenal crises. Corticosterone has some glucocorticoid activity; and elevated levels (ie, 50-100 times normal) are adequate to prevent adrenal insufficiency. Thus, these patients do not have hypoglycemia, hypotension, or difficulties dealing with infections, stress, or surgical procedures.
- These patients also experience no virilization or accelerated prepubertal growth as is typical in more common types of CAH that result from lack of sex steroids.
- Most patients have some degree of hypokalemia and hypertension; BP elevations range from mild to severe. Although 10-15% may have no hypertension or hypokalemia at presentation, an occasional patient may present with malignant hypertension or with severe, symptomatic hypokalemia.
Age
- Female patients usually are diagnosed upon presentation of delayed puberty or lack of menses.
- Males may go undiagnosed until puberty. These boys usually are raised as females and present to an endocrinologist for evaluation of lack of secondary sexual characteristics.
- Diagnosis may be suspected earlier in an infant with ambiguous genitalia or in an apparent female patient with a hernia or inguinal mass, hypertension, and hypokalemia.
History
- In general, patients have no problems with adrenal insufficiency and no history of adrenal crisis.
- Patients may have a history of hypertension, or hypertension may be the presenting complaint.
- Females
- Virilization and development of ambiguous genitalia do not occur in 46,XX patients with 17-hydroxylase (17-OH) deficiency.
- Unless hypertension is discovered, females may have no historical complaints or findings until puberty.
- The ovaries can secrete neither the androgens nor estrogens necessary for sexual maturation, and the adrenal glands cannot secrete androgens necessary for pubic and axillary hair growth. Consequently, adolescent females present with complaints of delayed puberty, primary amenorrhea, and lack of secondary sexual characteristics.
- Males
- The genitals of 46,XY 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.
Physical
- Mildly to severely elevated BP may be the primary finding.
- Females
- Affected 46,XX females have normal external and internal female differentiation; newborn females appear normal.
- 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.
- Males
- Genitals of affected males 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 normal-appearing female with lack of secondary sexual characteristics. Closer 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 an otherwise normal-appearing female infant or child, especially if combined with hypertension, suggests a diagnosis of 17-OH deficiency.
Causes
- 17-OH deficiency is inherited as an autosomal recessive trait.
- Recently, a common mutation within the CYP17 gene was identified in 2 Canadian patients from 2 apparently unrelated Mennonite families in Canada. This mutation also was found in 6 Mennonite families in the Netherlands.
5-Alpha-Reductase Deficiency
Ambiguous Genitalia and Intersexuality
Hypogonadism
Other Problems to be Considered
17,20 lyase deficiency
Lab Studies
- Male and female patients have no biochemical differences.
- All steroids requiring 17-hydroxylase (17-OH) activity for their production are found in very low concentrations. 17-OH Preg, 17-OH Prog, 11-deoxycortisol (compound S), cortisol, dehydroepiandrosterone (DHEA), androstenedione, and testosterone all are decreased or absent. The urinary metabolites 17-OH corticosteroid and 17-ketosteroid also are decreased or absent.
- Serum estrogens and urinary estrogens are low.
- Pregnenolone and progesterone levels are somewhat elevated; diagnosis is confirmed by markedly elevated levels of 11-deoxycorticosterone (11-DOC) and corticosterone.
- Aldosterone and plasma renin concentrations usually are low. DOC-mediated mineralocorticoid activity causes sodium retention and plasma volume expansion, with subsequent suppressed renin and aldosterone levels in most untreated patients.
- Within the pituitary, ACTH levels are elevated due to lack of cortisol secretion. The gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are elevated secondary to deficient sex steroid production by the gonads.
Other Tests
- 17-OH deficiency is inherited as an autosomal recessive trait similar to other forms of CAH. 17-OH, however, is not linked to the human leukocyte antigen (HLA) system. Detection of heterozygote carriers is difficult and requires biochemical rather than genetic criteria.
- Unstimulated levels of 11-DOC and corticosterone may be somewhat elevated in heterozygotes, and these individuals may have an exaggerated response to ACTH stimulation.
- Prenatal diagnosis of an affected infant is possible by measuring amniotic fluid concentrations of adrenal steroids.
Medical Care
- Exogenous glucocorticoid therapy is the treatment of choice. PO hydrocortisone (or other glucocorticoid) suppresses ACTH secretion and decreases 11-DOC and corticosterone levels.
- Potassium and BP abnormalities resolve after suppression of excessive mineralocorticoid activity, although some hypertension may persist for months to years in older or more severely affected individuals. Patients with this condition require additional antihypertension therapy.
- At puberty, male patients require sex steroid replacement (ie, testosterone). Female patients require cyclic estrogen-progesterone therapy. These therapies promote development of secondary sexual characteristics in both sexes and cyclic menstrual bleeding in 46,XX females.
Surgical Care
Perform a gonadectomy in 46,XY males who are raised as females; intra-abdominal testes carry a high risk of tumorous and malignant transformation.
Drug Category: Exogenous glucocorticoids
Exogenous glucocorticoid therapy suppresses ACTH secretion, decreases 11-DOC and corticosterone levels, and normalizes serum K levels and BP. Patients tend to respond to smaller doses of glucocorticoids than those required in other forms of congenital adrenal hyperplasia, possibly due to the glucocorticoid activity of endogenous corticosterone. Dosages are somewhat empirical and must be individualized based on clinical findings, growth, skeletal maturation, and hormonal data, including monitoring of 11-DOC and corticosterone levels.
| Drug Name | Hydrocortisone (Hydrocortone, A-Hydrocort) |
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| Description | DOC for infants and children. Longer-acting preparations (eg, prednisone, dexamethasone) are difficult to titrate and can lead to overtreatment and growth suppression. |
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| Pediatric Dose | Initial dose: 10-15 mg/m2/d PO divided tid; adjust long-term dose on individual basis |
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| Contraindications | Documented hypersensitivity; viral, fungal, or tubercular skin lesions |
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| Interactions | Live virus immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy for Addison disease; phenytoin, phenobarbital, ephedrine, and rifampin may increase hepatic clearance of steroids, requiring higher dosages; PT should be checked frequently in patients receiving glucocorticoids and coumarin anticoagulants since steroids may inhibit (or, rarely, enhance) response to these anticoagulants; when administered together with potassium-depleting diuretics, observe patients closely for possible hypokalemia |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Administer with meals to decrease GI upset; early onset adverse effects include glucose intolerance, hypertension, agitation, indigestion; late onset adverse effects include immune suppression, increased susceptibility to sepsis, hypertension, urinary calcium loss, osteopenia, gastric irritation, bleeding |
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Further Outpatient Care
- Evaluate infants and young children every 3-4 months for height, weight, BP, and concurrent laboratory monitoring of 11-DOC and corticosterone levels.
- A radiograph of the left hand may be obtained yearly to evaluate skeletal maturation.
- Adjust hydrocortisone dosages on an individual basis, determined by the results of the physical examination and laboratory studies.
- Sex hormone replacement is required at the age of expected puberty. (The mean age for the appearance of secondary sexual characteristics in the general population is 11.5-12.0 years for males and 10.5 years for females.) Start testosterone or estrogen administration at low doses and gradually increase as the child ages and matures.
In/Out Patient Meds
- Exogenous glucocorticoid therapy suppresses ACTH secretion, decreases 11-DOC and corticosterone levels, and normalizes serum potassium and BP. Hydrocortisone is the drug of choice for infants and children. Longer-acting preparations (eg, prednisone, dexamethasone) are difficult to titrate and can lead to overtreatment and growth suppression.
Prognosis
- Prognosis usually is good to excellent with adequate glucocorticoid therapy and monitoring.
- Patients rarely, if ever, have adrenal crises.
- Sex steroid replacement promotes development of secondary sexual characteristics in both sexes and cyclic menstrual bleeding in females.
- Hypertension sometimes may persist for months to years in older or more severely affected individuals, necessitating additional antihypertension therapy.
Patient Education
Medical/Legal Pitfalls
- Difficulties may arise when this relatively rare diagnosis is not considered, as in the following examples:
- Most patients with 17-hydroxylase (17-OH) deficiency syndrome have some degree of hypertension. Appropriate treatment consists primarily of exogenous glucocorticoid therapy; only more severely affected individuals require antihypertension medications. Failure to reach the proper diagnosis in such a patient may lead to inappropriate or incomplete treatment of the hypertension.
- Because patients may appear normal at birth and throughout childhood, female patients may not be diagnosed until they present at a later age with delayed puberty or amenorrhea. Appropriate treatment consists of exogenous sex steroid replacement plus glucocorticoid therapy. Failure to distinguish between 17-OH deficiency syndrome and other, more common causes of delayed puberty may lead to incomplete treatment.
Special Concerns
- Adults with 17-hydroxylase deficiency: While extensive literature and experience regarding treatment of pediatric patients exists, little has been published regarding treatment of adults with congenital adrenal hormone deficiencies. Certainly, no consensus or published guidelines exist regarding types, dosages, or timing of steroid replacement in adult patients. For example, a recent survey in the United Kingdom demonstrated that the most widely used glucocorticoid in adult patients was hydrocortisone, followed by dexamethasone and prednisolone. Sixty percent of physicians surveyed used larger doses of glucocorticoids at night (reverse circadian pattern) to achieve ACTH suppression, and only 16% of treating physicians used body weight or surface area to determine dosage. Adult patients must be continuously and carefully treated, using body size or weight-related dosages (in a manner analogous to pediatric treatment) to avoid extremes of over- and undertreatment.
| Media file 1:
Normal adrenal steroid biosynthesis results in 3 products—mineralocorticoids (aldosterone), glucocorticoids (cortisol), and androgens (androstenedione). Cortisol production is regulated by feedback with adrenocorticotrophic hormone (ACTH). ACTH stimulates the enzyme P-450scc (20,22 desmolase), with subsequently increased production of all adrenal steroids. |
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Media type: Graph
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| Media file 2:
Representation of typical congenital adrenal hyperplasia (CAH). This example shows a deficiency in both the mineralocorticoid and glucocorticoid pathways. Decreased serum cortisol levels stimulate adrenocorticotrophic 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. |
 | View Full Size Image | |
Media type: Graph
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| Media file 3:
C-17alpha-hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog). Absence of C-17alpha-hydroxylase impairs all sex steroid and cortisol production. Low levels of cortisol result in increased adrenocorticotrophic hormone (ACTH) stimulation of steroids prior to the 17-OH step, resulting in increased accumulation and secretion of 17-deoxysteroids by the zona fasciculata, including pregnenolone, progesterone, deoxycorticosterone (DOC), and corticosterone. |
 | View Full Size Image | |
Media type: Graph
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| Media file 4:
Graphic illustration of deficiency. Absence of C-17alpha-hydroxylase impairs all sex steroid and cortisol production. |
 | View Full Size Image | |
Media type: Graph
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- 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].
- Biglieri EG, Herron MA, Brust N. 17-hydroxylation deficiency in man. J Clin Invest. Dec 1966;45(12):1946-54. [Medline]. [Full Text].
- 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].
- Ducharme JR, Forest MG. Normal pubertal development. In: Pediatric Endocrinology: Physiology, Pathophysiology & Clinical Aspects. 2nd ed. 1993: 372-86.
- 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].
- Grumbach MM, Conte FA. Disorders of sex differentiation. In: Williams Textbook of Endocrinology. 8th ed. 1992: 853-951.
- 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].
- Kandemir N, Yordam N. Congenital adrenal hyperplasia in Turkey: a review of 273 patients. Acta Paediatr. Jan 1997;86(1):22-5. [Medline].
- Kater CE, Biglieri EG. Disorders of steroid 17 alpha-hydroxylase deficiency. Endocrinol Metab Clin North Am. Jun 1994;23(2):341-57. [Medline].
- Monig H, Sippell W. Congenital adrenal hyperplasia in adulthood: do men need to continue treatment?. Horm Res. 2005;64 Suppl 2:71-3. [Medline].
- Orth DN, Kovacs WJ, Debold CR. The adrenal cortex. In: Williams Textbook of Endocrinology. 8th ed. 1992: 489-619.
- 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].
- 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].
- 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].
17-Hydroxylase Deficiency Syndrome excerpt Article Last Updated: Jun 1, 2006
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