eMedicine Specialties > Endocrinology > Adrenal Gland

C-11 Hydroxylase Deficiency

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: Dec 30, 2008

Introduction

Background

Congenital adrenal hyperplasia (CAH) is a general term used to describe a group of inherited disorders in which a defect in cortisol biosynthesis is present with consequent overproduction of adrenocorticotropic hormone (ACTH) and secondary adrenal hyperplasia as a consequence. An enzymatic defect in 11-beta-hydroxylase is the second most common variant of CAH and accounts for approximately 5-8% of cases.

Patients with 11-beta-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children. Approximately two thirds of patients also have hypertension, which may or may not be associated with mineralocorticoid excess, hypokalemia, and metabolic alkalosis. The association of CAH with hypertension was first noted in the 1950s. The hypertension is initially responsive to glucocorticoid replacement, but it may become a chronic condition subsequently requiring standard antihypertensive therapy.

Pathophysiology

The zona fasciculata normally secretes cortisol, predominantly under the trophic effect of ACTH. The steroid biosynthetic pathway is shown in Image 1. Knowledge of this pathway is vital to understanding the clinical presentation of 11-beta-hydroxylase deficiency and the other variants of congenital adrenal hyperplasia (CAH).

In the zona fasciculata, the typical end product of the steroid biosynthetic pathway is cortisol (see Image 1), and cortisol regulates pituitary ACTH production through negative feedback inhibition. Loss of 11-beta-hydroxylase activity in the adrenal gland blocks the synthesis of cortisol and results in an increase in ACTH production. Aldosterone is the main mineralocorticoid produced by the adrenal zona glomerulosa, and its production is regulated by the renin-angiotensin system. A 17-hydroxy pathway similar to the active pathway in the zona glomerulosa exists in the zona fasciculata; however, the final product is corticosterone rather than aldosterone. Corticosterone is hydroxylated and oxidized at the 18 position to produce aldosterone in the glomerulosa, but not in the fasciculata.

The adrenal fasciculata production of corticosterone, a weak glucocorticoid, and deoxycorticosterone (DOC), a potent mineralocorticoid, is minimal and relatively unimportant in healthy normal individuals, but it is important in patients with 11-beta-hydroxylase deficiency. In these patients, a new steady state is achieved and excess DOC production occurs due to elevated ACTH levels.

Humans have two 11-beta-hydroxylase isoenzymes that are 93% identical. CYP11B1 is responsible for cortisol biosynthesis; it is expressed in the zona fasciculata and is regulated by ACTH. CYP11B2, which is responsible for aldosterone synthesis, is expressed in the zona glomerulosa and is regulated by the renin-angiotensin system and by potassium levels.¹ The genetic elements responsible for the differential regulation of CYP11B1 and CYP11B2 have not been elucidated completely. CAH due to 11-hydroxylase deficiency is due to genetic defects of CYP11B1 characterized by impaired conversion of 11-deoxycortisol to cortisol, reduced cortisol, impaired conversion of DOC to corticosterone, and increased 11-deoxycortisol, DOC, and ACTH secretion.^2,3

Mutations of the CYP11B2 gene cause aldosterone deficiency with characteristic features of mineralocorticoid deficiency.⁴ No associated cortisol deficiency or consequent adrenal hyperplasia is present, and isolated aldosterone synthetase deficiency is not a type of CAH.

Patients with 11-beta-hydroxylase deficiency have clinical features of androgen excess, such as premature sexual maturation observed in boys and virilization in females. These symptoms are the result of excess adrenal androgen production and are similar to those observed in the more common virilizing form of CAH, 21-hydroxylase deficiency. Accumulated cortisol precursors are shunted into the pathway of adrenal androgen production (see Image 1). Affected girls are born with some degree of virilization of their external genitalia, while the internal genital structures derived from the müllerian ducts (fallopian tubes, uterus, and cervix) are unaffected. Postnatally, both sexes may experience rapid somatic growth, accelerated skeletal maturation and premature development of sexual and body hair. Affected boys present with premature sexual maturation.

About two-thirds of patients with the severe (classic) variant of 11-beta-hydroxylase deficiency have early onset hypertension.⁵ This hypertension generally is mild to moderate, but in as many as one third of cases, it is associated ultimately with left ventricular hypertrophy, retinopathy, and macrovascular events. The exact cause of the hypertension is unclear and is presumed to be due to excessive secretion of DOC, a mineralocorticoid. Overall however, the degree of DOC excess does not correlate with the degree or severity of hypertension. Possibly, the 18-hydroxy and the 19-nor metabolites of DOC, which are mineralocorticoids, may play an additional role.

Rarely, patients with 11-beta-hydroxylase deficiency may have salt wasting, especially during infancy. The exact pathophysiology of this is unclear. In some cases, excess glucocorticoid administration appears to play a role through suppression of DOC secretion. If the zona glomerulosa is chronically suppressed by excess DOC, a sudden decrease in DOC associated with glucocorticoid therapy may not be compensated for by an adequate increase in aldosterone secretion. In cases that have been described prior to beginning therapy with glucocorticoids, the suggested mechanisms include abnormal sensitivity to the natriuretic effects of various putative natriuretic factors.

A milder, late-onset (nonclassic) form of CYP11B1 deficiency with symptoms of androgen excess is rare, but it has been described. Patients with this condition are not hypertensive. It is not a significant cause of hyperandrogenism in women, and stringent criteria should be used for diagnosis. ACTH-stimulated levels of 11-deoxycortisol should be at least 5 times the upper limit of normal levels to establish the diagnosis of nonclassic 11-beta-hydroxylase deficiency.

Frequency

United States

The prevalence of 11-beta-hydroxylase deficiency is approximately 1 case per 100,000 live births.

International

The international prevalence of 11-beta-hydroxylase deficiency is similar to US rates in most reported series worldwide. However, the reported rate in Jews from Morocco is much higher, being 1 case per 5000-7000 live births.⁶

Mortality/Morbidity

• The classic hypertensive variants of 11-beta-hydroxylase deficiency have the greatest potential for long-term morbidity.

Race

• 11-beta-hydroxylase deficiency is most commonly found in Jewish people of Moroccan descent.⁶

Sex

• Although 11-beta-hydroxylase deficiency is more easily recognizable in females, no sex predilection exists.

Age

• A genetic disease, 11-beta-hydroxylase deficiency affects patients throughout their life.
• The peak age at diagnosis is infancy and early childhood. Females present as neonates with ambiguous external genitalia, and males present as toddlers with virilization.
• The mild form of 11-beta-hydroxylase deficiency is rare and may present with menstrual irregularities and hirsutism in adolescent or adult women.

Clinical

History

• Virilization
  • Classic 46,XX patients present at birth with some degree of masculinization of their external genitalia.
  • Classic 46,XY patients typically present at 2-4 years of age with signs and symptoms of androgen excess, including increased growth velocity, advanced bone age, pubic hair, increased penile length, and aggressive behavior.
  • Later in life, males may have poor spermatogenesis that may manifest as azoospermia, oligospermia, and subsequent infertility.
  • Nonclassic 11-beta-hydroxylase deficiency is more subtle and presents later in life. Adolescent or adult females may present with amenorrhea, oligomenorrhea, or hirsutism.
• Hypertension⁵
  • Hypertension occurs in approximately two thirds of patients with the severe (classic) form of 11-beta-hydroxylase deficiency.
  • In these patients, hypertension often develops in the first few years of life. Because the blood pressure elevation is mild to moderate, comparing the blood pressures of patients to age-appropriate levels is vital.
  • Patients are usually asymptomatic.
  • Consequences of hypertension include left ventricular hypertrophy, retinopathy, cardiovascular accidents, and hypertensive nephrosclerosis.
  • Excess mineralocorticoids in patients can cause hypokalemia and metabolic alkalosis, which may present as muscle weakness and ileus.
  • Patients with mild (nonclassic) varieties of 11-beta-hydroxylase deficiency typically have normal blood pressure.
• Salt wasting
  • Salt wasting is a rare, but distinct, presentation.
  • Patients present with hyperkalemia, hyponatremia, and hypovolemia.
  • The exact pathophysiology is unclear, but it may be precipitated by glucocorticoid therapy.

Physical

• Ambiguous genitalia in XX patients are the most distinctive finding on physical examination.
  • The genital examination findings of XX patients vary depending on the degree of virilization.
  • Findings can include clitoromegaly that can be severe enough to simulate a male penis, or partial to full labioscrotal fold fusion that can simulate a scrotum (in the absence of palpable testicles).
  • Despite virilized external genitalia, patients who are 46,XX have normal female internal genitalia. For this reason, fertility is possible, and these patients should be raised as girls.
• In children, other signs of androgen excess include early puberty, pubic hair, axillary hair, adult body odor, and growth acceleration. Accelerated growth and early epiphysial fusion result in short stature as adults.
• Adult women may have signs of virilization, including muscular body habitus and hirsutism.
• Hyperpigmentation akin to that observed in Addison disease may occur due to the accompanying excess of ACTH. The hyperpigmentation may be more prominent at pressure points, around the areolae, the buccal mucosa or other mucous membranes, the scrotum, and scar tissue.
• Clinical features of uncontrolled hypertension, such as S₄, heart failure, elevated blood pressure, and hypertensive retinopathy, may be present.
• In affected young boys (aged 2-5 y), the phallus may have a greater length and thickness than are appropriate for the patients' chronologic age; these youngsters may also demonstrate advanced development of pubic and axillary hair. However, the testicular size in these boys tends to be small and firm (generally less than 5 mL in volume) and more consistent in size to their chronologic age. Palpable testicular masses in affected boys should raise the possibility of coexisting adrenal rest tumors. Apart from the testicles, these lesions can also arise in retroperitoneal locations, where they generally are clinically asymptomatic and often are first found through routine radiologic imaging tests.⁷

Causes

• An autosomal recessive disease, 11-beta-hydroxylase deficiency results from mutations in the CYP11B1 gene.² Moroccan Jews almost always show the same mutation—arginine (Arg) 448 to histidine (His) R448H.⁶
• Thus far, no consistent phenotype-genotype correlations have been made.³

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