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. It is also associated with compromised adult height.[1] 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.
The zona fasciculata normally secretes cortisol, predominantly under the trophic effect of ACTH. The steroid biosynthetic pathway is shown in the image below. 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). See the image below.
View Image
Steroidogenesis pathways in the adrenal cortex.
In the zona fasciculata, the typical end product of the steroid biosynthetic pathway is cortisol, as shown in the image above, 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.[2] 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.[3, 4, 5]
Mutations of the CYP11B2 gene cause aldosterone deficiency with characteristic features of mineralocorticoid deficiency.[6, 7] 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, as shown in the image above. 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.[8] 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.
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.[9]
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.[9]
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.[10]
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.
Hypertension[8]
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.
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.[11]
An autosomal recessive disease, 11-beta-hydroxylase deficiency results from mutations in the CYP11B1 gene.[3] Moroccan Jews almost always show the same mutation—arginine (Arg) 448 to histidine (His) R448H.[9]
Thus far, no consistent phenotype-genotype correlations have been made.[4]
Based on the excess precursors formed by the enzyme deficiency, diagnosis is made by measuring 11-deoxycortisol.[12]
Random levels of 11-deoxycortisol are markedly elevated (to several thousand ng/dL) in the classic form. In subjects with the late-onset (nonclassic) variants, random levels of 11-deoxycortisol may be normal; thus, an ACTH stimulation test to demonstrate elevated poststimulation values is then indicated (see Adrenocorticotropin [ACTH] and Dexamethasone/Corticotropin-Releasing Hormone Test).
In the classic form, other hormones that may be elevated include deoxycorticosterone (DOC), urinary 17-ketosteroids, urinary tetra hydrometabolites, adrenal androgens (including dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEA-S], and androstenedione), and testosterone.[13]
Because DOC and other precursors associated with 11-beta-hydroxylase deficiency have mineralocorticoid activity, plasma renin activity is suppressed.
Neonates may lack the diagnostic features of hypertension and suppressed renin.
Mild to moderate elevations of 17-hydroxyprogesterone may be observed (see 17-Hydroxyprogesterone, Serum and 17-Hydroxyprogesterone, Urine); thus, a diagnosis of 11-beta-hydroxylase deficiency may be missed in neonates if 11-deoxycortisol is not specifically measured. Although 17-hydroxyprogesterone levels are not markedly elevated, an erroneous diagnosis of 21-hydroxylase deficiency is possible.
In contrast to other forms of CAH, carriers of 11-beta-hydroxylase deficiency (heterozygotes) do not have elevated metabolite precursors.
Once a case has been identified, additional familial cases can be found by using biochemical or genetic markers.
Increased understanding of the genetic basis of this condition has enabled the medical community to establish the diagnosis prenatally.[14, 15, 16]
Techniques include estimating amniotic fluid 11-deoxycortisol and oligonucleotide hybridization of deoxyribonucleic acid (DNA) obtained from chorionic villus biopsies.
DNA analysis is used routinely in Israel, where the single His R448H mutation is prevalent.
In addition to enabling genetic counseling, prenatal diagnosis of 11-beta-hydroxylase deficiency offers the opportunity to consider prenatal treatment with dexamethasone in order to prevent virilization of the external genitalia of XX fetuses.[14, 15, 17]
In patients with a mild (nonclassic) variant of 11-beta-hydroxylase deficiency, ACTH-stimulated levels of 11-deoxycortisol should be 5 times the normal level.
Pelvic or testicular ultrasonography is useful to visualize adnexal structures in the pelvis of females, to check for normal gonads, and to exclude testicular masses.
Testicular adrenal rest tumors (ectopic adrenal tissue) have been described in males. The tumors usually are bilateral, located in the mediastinum testes, and detected by ultrasonography.
Abdominal computed tomography (CT) scanning may be useful for evaluating the adrenal glands, excluding mass lesions, and diagnosing adrenal hyperplasia, which typically is symmetrical and bilateral (and may also be nodular in long-standing cases). Occasionally, adrenal rests can also be found in ectopic retroperitoneal locations.
Treatment for 11-beta-hydroxylase deficiency is similar to that for all the other variants of congenital adrenal hyperplasia (CAH). It centers on suppressing the ACTH-driven adrenal hyperplasia and subsequent mineralocorticoid and/or androgen excess.
Glucocorticoid replacement therapy[18]
Glucocorticoid replacement is vital, because it reduces ACTH secretion and thus reduces the production of ACTH-dependent androgens and mineralocorticoids.
Clues that suggest inadequate glucocorticoid replacement include persistent hypertension, suppressed renin activity, elevated DOC or 11-deoxycortisol levels, and continued virilization in women or children.
Clues that suggest excess glucocorticoid replacement include obesity, decreased growth velocity in children, hyperlipidemia, osteoporosis, and suppressed 11-deoxycortisol levels.
Oral hydrocortisone is the ideal glucocorticoid for replacement therapy in children. A typical dose is 12-25 mg/m2/d in 2-3 divided doses.
Monitor patients for inadequate (virilization) and excess (cushingoid features) steroid treatment, even if the dose is within the indicated range.
If the response to hydrocortisone is poor, dexamethasone may be used in adults. The major problem associated with dexamethasone use is its relative short duration of action, which thus necessitates multiple daily dosing (ideally q4-6h). Other glucocorticoid formulations also may be used, and prednisone has a significantly longer duration of action than does dexamethasone, making bid to tid dosing adequate in most cases.
In situations involving fever or non–life-threatening illness, increase glucocorticoid dosages 2-3 times above the maintenance dose.
Treat patients with high doses of glucocorticoids for surgical procedures, life-threatening illness (eg, sepsis), and/or major trauma (hydrocortisone at 100 mg/m2 IV q6h as needed).
Antihypertensive therapy often is needed. Potassium-sparing diuretics, such as spironolactone or amiloride, with or without a calcium channel blocker, such as nifedipine, often are used.[19]
Prenatal treatment[14, 15, 17]
Prenatal treatment is an option for fetuses known to be at risk for classic 11-beta-hydroxylase deficiency. The only setting in which this therapy should be considered is if both parents are known carriers of virilizing CAH.
Prenatal therapy is controversial, because the long-term effects on the child are unknown.
Dexamethasone may be used in mothers during pregnancy at a dose of 20 mcg/kg/day in multiple divided doses initiated as soon as the pregnancy is confirmed, starting at approximately 4-5 weeks’ gestation.
Genetic testing is performed on the fetus, typically via chorionic villus sampling or less ideally by amniocentesis. Dexamethasone is discontinued if the fetus is XY or unaffected XX.
Once such therapy is initiated, the mother and fetus must be monitored closely. While this sort of therapy has the potential to reduce virilization in affected female babies, it does not obviate the need for subsequent CAH therapy in the child. In addition, the treatment's price is often great for the mother, because the required dose of dexamethasone invariably causes her to develop a cushingoid state.
Several preliminary trials of gene therapy for CAH in animal models of 21-hydroxylase deficiency are ongoing. Trials include gene transfer experiments in 21-hydroxylase–deficient mice and adenoviral vector/direct intra-adrenal transfer of the CYP21 gene in other animal models. At present, no human studies are underway.
Fertility and pregnancy[20]
Many women with congenital adrenal hyperplasia (CAH) wish to have children.
Reduced fertility may be caused by inadequately suppressed adrenal androgen production.[21]
Polycystic ovarian syndrome (PCOS) may develop secondary to adrenal hyperandrogenism.
The effect of ovarian exposure to adrenal androgens prenatally and during childhood is unknown, but it may predispose women with CAH to PCOS.
Other reasons for reduced fertility may include an inadequate vaginal vault for coitus and psychological factors leading to reduced sexual activity.[21]
Whether the increase in adrenal androgens associated with pregnancy requires increased glucocorticoid therapy is unclear. Placental aromatase appears to have a large reserve and is able to convert large amounts of ambient androgen to estrogen. This may prevent virilization of the fetus, even in cases of poorly controlled CAH in the mother.
Prednisone is the ideal glucocorticoid for use during pregnancy in patients with 11-hydroxylase deficiency and other CAH variants.
Dexamethasone or any other semisynthetic glucocorticoid crosses the placenta and suppresses the fetal hypothalamic-pituitary-adrenal (HPA) axis. This treatment should be used only when there is a high risk that a fetus will have virilizing CAH. In such a case, suppression of the fetal HPA axis is desirable.
During pregnancy, closely monitor glucocorticoid dosages and hormone levels.
Surgical care generally is limited to the reconstruction of ambiguous genitalia in female patients, a treatment that remains a subject of debate.[22]
The surgical procedure usually involves clitoroplasty and vaginoplasty in infancy, or clitoroplasty in infancy and vaginoplasty in late adolescence. Use of vaginal dilators sometimes is necessary to prevent restenosis.
Suggested treatment options for CAH have included the use of bilateral adrenalectomy. This has been proposed for infants, as well as for older patients. It is still considered experimental and should be reserved for cases that are difficult to control using standard medical therapy.
Because 11-beta-hydroxylase deficiency often is associated with ambiguous genitalia or precocious puberty, patients and families may require psychological counseling and support.
A small number of studies have suggested that women with CAH have a higher incidence of negative body self-image, have fewer sexual thoughts and fantasies, and are less sexually active. Endocrine, anatomical, surgical, and psychological factors may contribute to this observed reduction in sexual activity.[21]
The medical therapy for all variants of congenital adrenal hyperplasia centers on adequate glucocorticoid replacement.[18] This will reduce the ACTH-driven adrenal hyperplasia and production of the various hormone precursors. The recommended medications are hydrocortisone for children and hydrocortisone, prednisone, or dexamethasone for adults.
Potassium-sparing diuretics may be used. These agents are often not sufficient if hypertension is severe, in which case, calcium-channel blockers (nifedipine and verapamil) typically are used as first-choice antihypertensives.
Oral contraceptive pill preparations may be used in adult women with mild forms of the disease to ameliorate some of the virilizing symptoms associated with the condition.
Clinical Context:
Principal hormone secreted by the adrenal cortex. White, odorless, crystalline powder largely insoluble in water. Readily absorbed from the GI tract.
Clinical Context:
Synthetic adrenocortical steroid. Dexamethasone is a white, odorless, crystalline powder that is stable in air and practically insoluble in water. Lacks virtually any mineralocorticoid activity.
Clinical Context:
Calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) that selectively inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle without changing serum calcium concentrations. The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation by direct effects and resulting reduction in peripheral vascular resistance. Completely absorbed after oral administration. Extensively metabolized to highly water-soluble, inactive metabolites, accounting for 60-80% of the dose excreted in the urine. The elimination half-life is approximately 2 h. Only traces (< 0.1% of the dose) of unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, usually as a result of biliary excretion. Pharmacokinetics are not significantly influenced by the degree of renal impairment. Because hepatic biotransformation is the predominant route for the disposition of nifedipine, the
pharmacokinetics may be altered in patients with chronic liver disease. Because of reports suggesting their association with increased myocardial ischemia and cardiac mortality, the use of short-acting forms of nifedipine for acute and long-term blood pressure management is less popular and generally not preferable compared to using long-acting preparations, such as Procardia XL and Adalat CC.
This and other calcium-channel blockers (dihydropyridine and nondihydropyridine) have particular utility in the management of hypertension related to mineralocorticoid excess. They are among the most efficacious antihypertensives used in hypertension associated with congenital adrenal hyperplasia, such as that occurring in cases of 11-beta-hydroxylase deficiency.
Clinical Context:
Antikaliuretic diuretic agent. A pyrazine-carbonyl-guanidine that is chemically unrelated to other known antikaliuretic or diuretic agents. Potassium-conserving (antikaliuretic) drug that possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity. In some clinical studies, its activity increased effects of thiazide diuretics. Amiloride is not an aldosterone antagonist, and its effects are observed even in the absence of aldosterone. Exerts potassium-sparing effect through inhibition of sodium reabsorption at distal convoluted tubule, cortical collecting tubule, and collecting duct. This decreases the net negative potential of the tubular lumen and reduces potassium and hydrogen secretion, as well as their subsequent excretion.
Clinical Context:
Specific pharmacologic antagonist of aldosterone that acts primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule.
Complications result from inadequate or excess glucocorticoid therapy.
Inadequate glucocorticoid therapy in patients with 11-beta-hydroxylase deficiency could result in exacerbation of the symptomatology associated with the disease, including virilization in females, hyperpigmentation, and accelerated growth in early childhood (with consequent early epiphysial fusion and, thus, short adult stature).
For males, inadequate treatment could encourage the growth of adrenal rest tumors that, when present in the testicles, are known to be associated with oligospermia and consequently infertility.
The problems of virilization and precocious puberty associated with poorly treated cases also result in myriad adjustment, self-image, identity, and mood disorders that often require long-term treatment and counseling by mental health professionals.
Patients with a poorly controlled condition may also have poorly controlled hypertension and the well-known cardiovascular sequelae.
Excessive glucocorticoid therapy is also associated with a litany of potential medical problems, as typified in patients with Cushing syndrome. Among the major conditions that must be carefully looked for are truncal obesity, poor wound healing, osteoporosis, chronic insomnia, and an increased risk for diabetes, dyspeptic ulcer disease with bleeding, and glaucoma.
Patients should wear medic alert bracelets stating the potential for adrenal insufficiency.
Patients should have emergency intramuscular hydrocortisone at home. The patient and family members should be properly educated in its administration in case oral intake is not possible.
Patients should know the features of glucocorticoid excess and glucocorticoid deficiency and should receive education in the early detection of these conditions.
Gabriel I Uwaifo, MD, Associate Professor, Section of Endocrinology, Diabetes and Metabolism, Louisiana State University School of Medicine in New Orleans; Adjunct Professor, Joint Program on Diabetes, Endocrinology and Metabolism, Pennington Biomedical Research Center in Baton Rouge
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
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
Disclosure: Nothing to disclose.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Ghassem Pourmotabbed, MD, MD,
Disclosure: Nothing to disclose.
Acknowledgements
Deborah P Merke, MD, Chief of Pediatric Services, Pediatric and Reproductive Endocrinology Branch, Warren Grant Magnuson Clinical Center; Clinical Investigator, National Institute of Child Health and Human Development, contributed to this article.
Azziz R. Nonclassic adrenal hyperplasia. Bardin CW, ed. Current Therapy in Endocrinology and Metabolism. 6th ed. St Louis, Mo: Mosby-Yearbook; 1997. 175-8.
New MI, Newfield RS. Congenital adrenal hyperplasia. Bardin CW, ed. Current Therapy in Endocrinology and Metabolism. 6th ed. St Louis, Mo: Mosby-Yearbook; 1997. 179-187.
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