eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

17-Hydroxylase Deficiency Syndrome

Author: J Paul Frindik, MD, FACE, Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences
Contributor Information and Disclosures

Updated: Sep 24, 2008

Introduction

Background

17-hydroxylase (17-OH) deficiency syndrome is a rare genetic disorder of steroid biosynthesis that causes 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 are usually 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 the following 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 is also directly stimulated 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 Media file 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 that do not require the missing enzyme (ie, build-up of compounds both before the block and "sideways" from the block). See Media file 2. Treatment with exogenous glucocorticoid decreases ACTH secretion and subsequent suppression of overproduced steroids.

Cytochrome P450c17, an enzyme complex present in Leydig cells, ovarian follicles, and the adrenal zonae fasciculata and reticularis, catalyzes both 17-hydroxylase and 17,20 lyase activity. P450c17 is the product of the CYP17A1 gene, and specific mutations of this gene cause varying degrees of partial-to-severe isolated 17-hydroxylase deficiency, isolated 17,20 lyase deficiency, or combined deficiencies.^1,2,3,4  
 
A rare cause of 17-hydroxylase deficiency syndrome is autosomal recessive P450 oxidoreductase (POR) deficiency. POR is an obligate electron donor for all microsomal P450 enzymes, including P450c17 (17 α -hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450 aro (aromatase). POR deficiency affects multiple steroidogenic pathways.^5,6

C-17 α -hydroxylase is necessary to convert pregnenolone to 17-hydroxypregnenolone (17-OH Preg) and progesterone to 17-hydroxyprogesterone (17-OH Prog); see Media file 3. Thus, absence of this enzyme impairs all sex steroid and cortisol production (see Media file 4). Low levels of cortisol result in increased 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 (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-hydroxylase deficiency.

In order to better define the molecular basis of 17-hydroxylase deficiency, genetic analysis was performed on 19 families with 17-hydroxylase deficiency.⁷ Seven different CYP17 mutations were found among 24 subjects. However, 2 mutations accounted for most cases: W406R (50%) and R362C (32%). In these families, phenotypic features varied among the subjects and did not correlate with the CYP17 genotype. 

Frequency

International

Approximately 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-β -hydroxylase deficiency, has an incidence of about 1 in 100,000 (see C-11 Hydroxylase Deficiency). 17-hydroxylase deficiency is probably even more rare. Some estimate the occurrence of 17-hydroxylase deficiency at approximately 1 case per 50,000 individuals.

17-hydroxylase deficiency occurs worldwide. However, individuals with severe, confirmed 17-hydroxylase deficiency are rare, and most reported 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;⁸ Brazil, where 16 cases were reported over a 10-year period;⁷ ; and Puerto Rico, where 1 case was reported.⁹

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; blood pressure elevations range from mild to severe. Although 10-15% may have no hypertension or hypokalemia at presentation, patients may present with malignant hypertension or with severe, symptomatic hypokalemia.

Age

Female patients are usually diagnosed upon presentation of delayed puberty or lack of menses. Males may go undiagnosed until puberty. These boys are usually 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.

Clinical

History

In general, patients with 17-hydroxylase (17-OH) deficiency have no history of adrenal insufficiency nor adrenal crisis. Patients may have a history of hypertension, or hypertension may be the presenting complaint. Both the age of onset and degree of severity of hypertension seem to vary between patients.²

• Females
  • 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,¹⁰ , and lack of secondary sexual characteristics.
• Males
  • 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.

Physical

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

• 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-hydroxylase deficiency.

Patients with P450 oxidoreductase (POR) deficiency have varying degrees of adrenal insufficiency and genital anomalies. In addition, most have skeletal malformations including craniosynostosis, radio-ulnar synostosis, midface hypoplasia, and bowed femurs (Antley-Bixler syndrome).^5,6

Causes

17-hydroxylase deficiency is inherited as an autosomal recessive trait. 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.¹¹

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