Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

A guide for patients and their families

The Johns Hopkins Children's Center

Prepared by:
Claude J. Migeon, M.D. and Amy B. Wisniewski, Ph.D.
Department of Pediatrics
Division of Pediatric Endocrinology
Johns Hopkins Hospital, Baltimore, MD
Comments and Suggestions Provided by: John P. Gearhart, M.D. and Carol Saucier, R.N., M.S.N.

What is Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency?

Congenital Adrenal Hyperplasia (CAH) includes a group of disorders, each characterized by a deficiency of one of the enzymes needed to make the hormone cortisol.

Cortisol is a steroid hormone necessary to the following body functions:

There are several different forms of CAH, each related to one of the enzymes necessary to transform cholesterol to cortisol (hydrocortisone). These enzymes are: StAR / 20,22-hydroxylase, 3-hydroxysteroid-dehydrogenase / 17-hydroxylase / 21-hydroxylase and 11-hydroxylase.

When one of these enzymes is deficient, this leads to a hyperfunction and increased size (hyperplasia) of the adrenals, hence the name Congenital Adrenal Hyperplasia. Among the various forms of CAH, the 21-hydroxylase deficiency is by far the most frequent, representing more than 90% of all cases.

This is the only form to be discussed here. First, normal adrenal function will be presented, followed by a discussion of adrenal function in 21-hydroxylase deficiency and its treatment.

I. Normal Adrenal Function

The adrenal glands are located above each kidney. Each adrenal gland is made up of two regions, the inner region (called the medulla) which produces adrenaline and the outer region (called the cortex) which produces adrenal steroid hormones. Three types of adrenal steroids are produced; glucocorticoids ("sugar hormones"), mineralocorticoids ("salt-water hormones") and androgens ("male hormones"). It is these hormones which are produced in abnormal amounts in people with CAH.

A. Cortisol

The normal production of adrenal hormones results from a multi-step chain of events that occurs between the brain and the adrenal glands. The pituitary gland located at the base of the brain produces the AdrenoCorticoTropic Hormone (ACTH) which activates the adrenal glands to produce cortisol. Cortisol and ACTH work "in balance" - when cortisol in the blood is too high, it "turns off" additional ACTH production, hence returning cortisol production to normal. In contrast, when cortisol in the blood is too low, ACTH production increases until cortisol concentrations return to normal.

It is important to remember that cortisol production doubles or triples at the time of medical, surgical or psychological stress.

B. Aldosterone

Aldosterone (salt - water hormone) secretion is under the control of another hormone, angiotensin, which itself is under control of the hormone renin produced by the kidneys. When aldosterone is too low, salt (NaCl) levels in the blood fall as does total body water. This leads to an increase in renin, which then causes an increase in angiotensin production, and subsequently a return of aldosterone concentrations back to normal. When aldosterone is too high, serum sodium, total body water and blood pressure increase, resulting in decreased renin and angiotensin production until aldosterone returns to normal.

C. Adrenal Androgens

During fetal life prior to birth a large amount of adrenal androgen is secreted in both males and females. At 3-6 months after birth, secretion of adrenal androgen stops.

During puberty, adrenal androgen secretion resumes in both boys and girls. These androgens are responsible for the development of pubic and axillary hair in girls. In boys, the production of testicular androgens (which is about 10 times more active than adrenal androgens) play the major role in male masculinization.

II. Adrenal Function And 21-Hydroxylase Deficiency

It is typical to distinguish three forms of 21-hydroxylase deficiency which, in order of severity, are: the salt-losing form (most severe), the simple-virilizing form (moderate severity) and the late-onset or nonclassical form (least severe).

A. Salt-Losing Form of CAH

There is a total or near-total deficiency of the 21-hydroxylase enzyme. This results in the complete inability to produce cortisol and aldosterone.

The body's total inability to produce cortisol leads to an increase in ACTH and a build-up of precursors to cortisol (i.e., 17-hydroxyprogesterone and androgens).

Aldosterone production is also impaired due to the total absence of 21-hydroxylase. Although there is an increase in both renin and angiotensin, aldosterone productions remains low or nonexistent.

B. Simple-Virilizing Form of CAH

This refers to a partial deficiency of the 21-hydroxylase enzyme. Because this enzyme deficiency is only partial, these subjects are able to produce near normal or normal amounts of cortisol due to of increased ACTH output. However, similar to the salt-losing patients, simple-virilizing patients experience an increase in the production of 17-hydroxyprogesterone as well as adrenal androgens. The elevated 17-hydroxyprogesterone produces a salt-losing tendency. Because the 21-hydroxylase deficiency is partial, the adrenals are able to increase production of aldosterone to compensate for salt loss.

C. Adrenal Androgens in Salt-Losing & Simple-Virilizing CAH

In both forms of CAH, the increased production of adrenal androgens is of concern.

The most important adrenal androgen secreted in large amounts is androstenedione. This steroid is not androgenic by itself. However, approximately 10% of androstenedione is metabolized in the body to testosterone, a potent androgen.

Excess androgen production during fetal life, associated with salt-losing and simple-virilizing CAH, masculinizes the external genitalia of female infants. This includes an enlargement of the clitoris and variable degrees of fusion of the labia.

The simple virilizing form of CAH results in a moderate excess of androgen production with moderate masculinization of the external genitalia in females. Salt-losing CAH results in greater masculinization than simple-virilizing CAH due to greater production of androgens.

D. Nonclassic or Late-Onset Form of CAH

Late-onset CAH refers to a mild deficiency of the 21-hydroxylase enzyme. People with late-onset CAH start to exhibit symptoms related to excess androgen production in childhood or adolescence. Because the 21-hydroxylase deficiency is mild, patients are able to produce normal amounts of cortisol and aldosterone. However, affected individuals produce increased amounts of cortisol precursors (17-hydroxyprogesterone) and adrenal androgens. In boys and girls, this results in rapid growth and early virilization. In girls, this can also result in masculinization and abnormal menses.

III. CAH WITHOUT TREATMENT

Cortisol and aldosterone are necessary to life. Prior to the availability of salt-retaining hormones and glucocorticoids, infants with complete 21-hydroxylase deficiency (salt - losing form) died shortly after birth as a result of a salt-losing crisis.

In the simple-virilizing form, cortisol is normal or near normal and aldosterone can increase to compensate for the salt losing tendency. Hence, these infants can survive despite lack of treatment. However, both girls and boys are subjected to progressive masculinization.

This includes the early appearance of body hair, acne and increased musculature in both sexes. At puberty, normal feminization of girls fails to occur (no breast development, no menstruation). For women left untreated, fertility is compromised due to the absence of ovulation. In both sexes, the large amount of androgens produce rapid growth in height, but also early bone maturation resulting in short stature at adulthood.

IV. CAH WITH TREATMENT

CAH cannot be cured, but it can be effectively treated. Modalities of treatment were established in the early 1950's at Johns Hopkins Hospital in Baltimore and at Massachusetts General Hospital in Boston. The principle of therapy is to administer an amount of cortisol approximately equal to the normal production of this steroid. The result is suppression of ACTH and consequently suppression of adrenal function. Putting the adrenal "at rest" results in total suppression of cortisol precursors (including androgens).

In salt losers, it is also necessary to administer salt-retaining hormone treatment (florinef) to compensate for the aldosterone deficiency. In all forms of 21-hydroxylase deficiency, it is most important to double or triple the baseline dose of cortisol at times of stress.

V. SPECIFICS OF ENDOCRINE TREATMENT

The following section is meant to inform patients and parents about endocrine guidelines for treatment of 21-hydroxylase deficiency. While it is important for patients to be informed about the type of treatment they receive, this information is not meant to take the place of regular visits to a Pediatric or Adult Endocrinologist. Every patient is different, and as a result treatment guidelines often need to be "custom-tailored" to fit individual needs.

A. Glucocorticoids

As already noted, the goal is to administer a dose of hormone equal to normal cortisol production. Cortisol production varies greatly among individuals, from 8 to 14 mg per square meter of body surface area every 24 hours.

1. Cortisol treatment

The oral preparations available include Cortef tablets (5,10 or 20 mg.) and Cortef suspension (2 mg. of cortisol per 1 ml). Because gastric acid destroys some of the oral cortisol, the treatment dose must be about twice that of normal production (15 to 30 mg per square meter of body surface area every 24 hours).

Due to rapid disappearance of cortisol from blood, it is necessary to administer 1/3 of a daily dose three times a day (5 to 10 mg per square meter of body surface area, every 8 hours, by mouth).

2. Prednisolone treatment

Prednisolone is about 5 times more active than cortisol (Pediapred syrup contains 1 mg prednisolone per 1 ml). Hence, the daily dose is 3 to 6 mg per square meter of body surface area every 24 hours orally. Because prednisolone has a longer half-life in blood than cortisol, 1/2 the daily dose can be administered twice per 24 hour period (1.5 to 3 mg per square meter of body surface area, twice daily).

3. Glucocorticoids during stress

If a person with CAH is sick with a fever of 101°F or higher, or has a serious injury (such as a broken bone), he or she may need additional glucocorticoid treatment. If surgery is planned, glucocorticoid treatment will probably be increased before, during and after the surgery.

With a temperature of 101°F, a triple baseline dose is recommended for the period of stress. It is important to limit the stress dose to the period of stress in order to avoid symptoms of over-treatment. You should discuss with your doctor or nurse the appropriate guidelines for increasing glucocorticoid treatment.

4. Glucocorticoids in conditions of repeated vomiting

If a person with CAH vomits their oral medicine, an increased oral dose should be administered 30 minutes after vomiting. If this in turn is vomited, a cortisol injection is needed. Other circumstances in which affected individuals may need to receive their treatment via injection is if they are unconscious, have severe diarrhea, or are unable to take anything by mouth prior to surgery.

Injectable hydrocortisone is sold as Solu-Cortef (Acti-Vial) and should be kept in the home for emergency use. Your nurse or doctor will show you how to mix the vial of Solu-Cortef and give it as a shot. Give 25 to 100 mg Solu-Cortef via intramuscular injection. This provides a window of approximately 6 hours to get to an Emergency Room.

People with salt-losing CAH lose salt rapidly with vomiting and diarrhea. Florinef cannot be administered as an injection, but injected cortisol (Solu-Cortef) has some salt-retaining action. A triple baseline dose of cortisol produces adequate salt retention. Additionally, a salt-water solution can be administered intravenously, if needed, in an emergency room.

5. Medic-Alert

Because a person may not alwys be able to administer their own treatment (i.e. they are too young, they are unconscious), people with CAH are stongly advised to wear a medical identification bracelet or necklace (Medic-Alert) stating that he or she takes glucocorticoids and Florinef. This notifies medical personnel to administer stress doses of treatment if needed. For more information about Medic-Alert jewelry, refer to the following address:

B. Salt-retaining hormone

The only available preparation for salt-retaining hormone treatment is Florinef (9-fluoro-hydrocortisone), 0.1 mg tablets. The daily dose varies from 0.05 to 0.15 mg daily, taken once a day orally. In contrast to the cortisol dose, the Florinef dose does not vary according to age or body size of the patient.

C. Added Salt

Typically, normal infant food is low in salt (about 10-12 mEq of sodium). Infants with salt-losing CAH may profit from added salt to their diet until they begin to eat table food which has a higher salt content.

VI. Monitoring Treatment

Because of large individual variation in cortisol secretion, it is important to monitor treatment very carefully. The means to determine an appropriate replacement dose includes measurement of plasma 17-hydroxyprogesterone and androstenedione concentrations, or of the urinary excretion of pregnanetriol (the major metabolite of 17-hydroxyprogesterone) and 17-ketosteroids (the metabolites of androgens). It is also important to follow growth (Bone Age and Height Age) in order to monitor the anabolic effects of adrenal androgens.

Finally, it is necessary to check serum electrolytes frequently to assure normal levels of sodium, potassium and CO₂. This is particularly important for salt-losers.

VII. Surgical Treatment For Female Patients

In most female patients, CAH treatment also includes surgical correction of the masculinized external genitalia and lengthening and opening of the vagina.

At 3-6 months of age, efforts are usually made to feminize the appearance of the external genitalia if marked enlargement of the clitoris has occurred. This is accomplished by reducing the size of the phallus to make it look like a clitoris. Presently, this involves the removal of the posterior part of the corpora and the repositioning of the glans, while maintaining the nerves and blood vessels supplying the glans.

While some doctors believe that vaginoplasty can be performed in infancy, others believe the best time for vaginal surgery is during adolescence, when the patient is ready to engage in sexual activity

VIII. Psychological Treatment

Many individuals with CAH report benefits as a result of discussing their medical situation with a person who is knowledgeable about their condition. Topics of particular concern to some CAH patients are gaining an understanding of their medical condition, and the life-long requirement of medication for normal growth, pubertal development, fertility (for women), genital surgery (for women) and sexuality. There is no absolute recommendation for how much counseling is needed by CAH patients. Counseling can be helpful once sexual development and activity begin, and also when it is time to start family planning. Additionally, for girls and women, a counselor can be tremendously helpful during times of genital surgery.

Like all treatment guidelines, counseling guidelines must be adapted to meet the needs of any particular person. Typically, however, it is helpful to establish a person (pediatric endocrinologist, counselor, psychologist, nurse) who is both knowledgeable about CAH and with whom the patient feels comfortable, to discuss these types of issues should the need arise.

IX. Genetics of CAH

21-hydroxylase is an enzyme made by a gene located on the short arm of chromosome 6. This gene is located in an area of the chromosome that contains many other important genes whose products control immune function.

Various mutations of the 21-hydroxylase gene result in various degrees of CAH (e.g., salt-losing form, simple-virilizing form, nonclassic form). The frequency of 21-hydroxylase mutations in the general population is about 1 in 60 people. In other words, among a group of 60 women, one is likely to have a 21-hydroxylase mutation on one of her two copies of chromosome 6. Similarly, among a group of 60 men, one is likely to have a mutation on one of his two copies of chromosome 6 as well. People with a mutation on one of their two copies of chromosomes are called "carriers" (they are heterozygous for the mutation) but have no problems with their adrenal function.

When two carriers have children, there is a 25% chance that each will contribute their mutant chromosome 6 to the child. There are four possible outcomes for each pregnancy resulting from two carrier parents:

Only the child who receives two copies of mutant chromosome 6 (one from the mother and one from the father) will be affected by CAH (these individuals are homozygous for the mutation).

X. Other Sources of Information

Internet Sites for CAH Patients and Families

The Magic Foundation

National Adrenal Diseases Foundation (NADF)

This Site: (www.med.jhu.edu/pedendo/cah/)

Glossary

21-hydroxylase:

An enzyme needed to produce cortisol and aldosterone.

21-hydroxylase deficiency:

The most common type of enzyme deficiency that results in congenital adrenal hyperplasia (CAH).

ACTH:

Abreviation for adrenocorticotropic hormone. It activates cortisol production.

Aldosterone:

A hormone secreted by the adrenal glands, important in maintaining salt and water balance in the body.

Androgens:

A group of steroid hormones that cause masculinization.

Androstenedione:

A type of androgen produced by the adrenal glands which is partially transformed by the body into testosterone.

Angiotensin:

This compound activates production of aldosterone. Production of angiotensin is controlled by RENIN.

Cholesterol:

A precursor of all steroid hormones (androgens, estrogens, glucocorticoids).

Corpora:

The main part of the phallus (clitoris or penis).

Cortex:

The outer portion of an organ.

Cortisol:

A steroid secreted by the adrenal cortex, important for maintaining blood sugar levels, maintenance of body fluids and electrolytes, and protecting the body from stress.

Cortisone:

A steroid similar to cortisol.

Electrolytes:

Salts found in body fluids.

Glans:

The conical portion of the tip of the phallus (clitoris or penis).

Glucocorticoids:

Cortisol - like steroid hormones secreted from the adrenal cortex, important for many bodily functions including response to stress, maintenance of blood sugar levels, body fluids and electrolytes.

Glucocorticoid Therapy:

Replacement cortisol administered when the body is unable to produce adequate amounts.

Hormone:

A chemical secreted by a gland, into the blood which travels to all parts of the body.

Late-onset (Non Classical) CAH:

The mildest form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, charcterized by increased androgen production.

Medulla:

The middle portion of an organ.

Mineralocorticoids:

Aldosterone - like steroid hormones secreted from the adrenal cortex, important for maintenance of salt and water balance.

Phallus:

A penis. Whan a clitoris is enlarged, it is referred to as a phallus because it resembles a penis.

Pituitary Gland:

A gland located at the base of the brain that produces ACTH and several other protein hormones.

RENIN:

An enzyme produced by the kidneys, necessary for the production of angiotensin.

Salt-Losing CAH:

The most severe form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, characterized by decreased or absent production of cortisol and aldosterone and increased adrenal androgen production.

Simple-Virilizing CAH:

A moderately severe form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, characterized by increased adrenal androgen production and normal or close to normal cortisol production.

Steroid:

A class of hormones produced from the precursor cholesterol which share certain structural characteristics.

Stress:

The body's reaction to mental or physical challenges.

Testosterone:

A steroid hormone produced by the adrenal glands and testes or converted from androstenedione, which can exert masculinizing effects.