Congenital Adrenal Hyperplasia

Definition

Congenital adrenal hyperplasia (CAH) is a genetic disorder characterized by a deficiency in the hormones cortisol and aldosterone and an over-production of the hormone androgen. CAH is present at birth and affects the sexual development of the child.

Description

Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency in which 21-hydroxylase, the enzyme that produces two important adrenal steroid hormones, cortisol and aldosterone, is deficient. Because cortisol production is impeded, the adrenal gland over-produces androgens (male steroid hormones). CAH affects both females and males. Females with CAH are born with an enlarged clitoris and normal internal reproductive tract structures. Males have normal genitals at birth. CAH causes abnormal growth for both sexes; those affected will be tall as children but short as adults because of early bone maturation. Females develop male characteristics, and males experience premature sexual development.

In its most severe form, called salt-wasting (or salt-losing) CAH, where there is a total or near total deficiency of the 21-hydroxylase enzyme, a life-threatening adrenal crisis can occur if the disorder is untreated. Adrenal crisis can cause dehydration, shock, and death within 14 days of birth. There is also a milder form of CAH in which children have partial 21-hydroxylase enzyme deficiencies (simple virilizing form). Another type of CAH is characterized by only a slight deficiency in production of the 21-hydroxylase enzyme (nonclassic or late-onset form), in which symptoms occurs later in childhood or during young adolescence.

CAH is also called adrenogenital syndrome or 21-hydroxylase deficiency.

Demographics

CAH, a genetic disorder, is the most common adrenal gland disorder in infants and children, occurring in one in 10,000 total births worldwide.

Causes and symptoms

CAH is an inherited recessive disorder, which means that a child must inherit one copy of the defective gene from each parent who is a carrier; when two carriers have children, each pregnancy carries a 25 percent risk of producing an affected child. CAH is related to the deficiency of 21-hydroxylase, an enzyme that is required to transform cholesterol into cortisol. The 21-hydroxylase gene is 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 (salt-losing form, simple-virilizing form, and the nonclassic form). When 21-hydroxylase is deficient, this leads to a hyperfunction and increased size (hyperplasia) of the adrenals.

In females, CAH produces an enlarged clitoris at birth, with the urethral opening at the base (ambiguous genitalia, appearing more male than female) and masculinization of features as the child grows, such as deepening of the voice, facial hair, and failure to menstruate or abnormal periods at puberty. The internal structures of the reproductive tract, including the ovaries, uterus, and fallopian tubes, are normal. Females with severe CAH may be mistaken for males at birth. In males, the genitals are normal at birth, but the child becomes muscular, the penis enlarges, pubic hair appears, and the voice deepens long before normal puberty, sometimes as early as two to three years of age. At puberty, the testes are small.

In the severe salt-wasting form of CAH, newborns may develop symptoms shortly after birth, including vomiting, dehydration, electrolyte (a compound such as sodium or calcium that separates to form ions when dissolved in water) changes, and cardiac arrhythmias. If not treated, this form of CAH can result in death within one to six weeks after birth.

In the mild form of CAH, which occurs in late childhood or early adulthood, symptoms include premature development of pubic hair, irregular menstrual periods, unwanted body hair, or severe acne. However, sometimes there are no symptoms, and children affected are diagnosed because of an affected relative.

When to call the doctor

Many cases of CAH will be detected at birth, but in milder cases, symptoms may not develop until later, at which time medical care should be obtained. For children with more severe cases of CAH, regular medical care is necessary to achieve desired treatment results.

Diagnosis

CAH is diagnosed by a careful examination of the genitals and blood and urine tests that measure the hormones produced by the adrenal gland. A number of states in the United States perform a hormonal test (a heel prick blood test) for CAH and other inherited diseases within a few days of birth. In questionable cases, genetic testing can provide a definitive diagnosis. For some forms of CAH, prenatal diagnosis is possible through chronic villus sampling in the first trimester and by measuring certain hormones in the amniotic fluid during the second trimester.

Treatment

The goal of treatment for CAH is to return the androgen levels to normal. This is usually accomplished through drug therapy, although surgery may be an alternative for children with little or no enzyme activity. Lifelong treatment for CAH is required.

Drug therapy consists of use of a cortisol-like steroid medications called glucocorticoids. Oral hydrocortisone is prescribed for younger children, and prednisone or dexamethasone is prescribed for older children. Side effects of steroids include stunted growth. Steroid therapy should not be suddenly stopped, since adrenal insufficiency will result. Treatment results must be monitored carefully, because of large individual variations in enzyme deficiency in children with CAH.

For children with salt-wasting CAH, fludrocortisone (Florinef), which acts like aldosterone (the missing hormone), is also prescribed. Infants and small children may also receive salt tablets, while older children are encouraged to eat salty foods. Serum electrolytes must be checked frequently, especially for children with salt-wasting CAH, to assure that normal levels of sodium and potassium are maintained.

Medical therapy achieves hormonal balance most of the time, but at times appropriate levels can be hard to maintain. CAH patients may have periods of fluctuating hormonal control that lead to increases in the dose of steroids prescribed. Sometimes these doses can become excessive as needs later decrease, leading to growth inhibition.

Increased doses may also be required when the child has a fever or a serious injury (a broken bone). If children are vomiting their oral medicine, have severe diarrhea, are unconscious, or cannot take anything by mouth before surgery, they may need to receive their medications by injections.

Children with CAH should see a pediatric endocrinologist frequently. The endocrinologist will assess height, weight, and blood pressure, and order an annual x ray of the wrist (to assess bone age), as well as assess blood hormone levels. If they require medical treatment, CAH children with the milder form of the disorder are usually effectively treated with hydrocortisone or prednisone.

Females with CAH who have masculine external genitalia require surgery to reconstruct the clitoris and/or vagina. This is usually performed when the child is an infant. However, some doctors and parents believe that the best time for vaginal surgery is during adolescence.

An experimental type of drug therapy—a three-drug combination, with an androgen blocking agent (flutamide), an aromatase inhibitor (testolactone), and low dose hydrocortisone—was as of 2004 being studied by physicians at the National Institutes of Health. Preliminary results are encouraging, but it will be many years before the safety and effectiveness of this therapy is fully known.

Adrenalectomy, a surgical procedure to remove the adrenal glands, is a more radical treatment for CAH. It was widely used before the advent of steroids. In the early 2000s, it is recommended for CAH children with little or no enzyme activity and can be accomplished by laparoscopy. This is a minimally invasive type of surgery done through one or more small one-inch (2.5 cm) incisions and a laparoscope, an instrument with a fiber-optic light containing a tube with openings for surgical instruments. Adrenalectomy is followed by hormone therapy, but in lower doses than CAH patients not treated surgically receive.

Prognosis

CAH can be controlled and successfully treated in most patients as long as they remain on drug therapy.

Prevention

Prenatal therapy, in which a pregnant woman at risk for a second CAH child is given dexamethasone to decrease secretion of androgens by the adrenal glands of the female fetus, has been in use since 1994. This therapy is started in the first trimester when fetal adrenal production of androgens begins but before prenatal diagnosis is done that would provide definitive information about the sex of the fetus and its disease status. This means that a number of fetuses are exposed to unnecessary steroid treatment in order to prevent the development of male-like genitals in female fetuses with CAH. Several hundred children have undergone this treatment with no major adverse effects, but its long-term risks are unknown. Since there is very little data on the effectiveness and safety of prenatal therapy, it should only be offered to patients who clearly understand the risks and benefits and who are capable of complying with strict monitoring and follow-up throughout pregnancy and after the child is born.

Parental concerns

Parents with a family history of CAH or who have a child with CAH should seek genetic counseling. Genetic testing during pregnancy can provide information on the risk of having a child with CAH.

Because children with CAH may not always be able to administer their own treatment (because they are too young or they are unconscious), parents are encouraged to make sure that the child with CAH wears a medical identification bracelet or necklace (Medic-Alert) stating that the child takes glucocorticoids and possibly Florinef. This notifies medical personnel to administer stress doses of medicines if needed.

When taking a child with CAH for emergency care, parents are advised to refer to the condition by its full name rather than CAH. This is because this rare disease could be confused with another condition that shares the same initials: chronic active hepatitis. The parents should inform medical personnel if the child has salt-wasting CAH. It is also recommended that parents have a letter or information prepared concerning CAH and care needed so that this can be given to a new doctors who may treat the child.

Parents should be sensitive to the psychological aspects of the disease and obtain counseling for children with CAH. Topics of concern might include an understanding of the disease, the life-long requirement for medication, genital surgery, and sexuality.

BOOKS

Congenital Adrenal Hyperplasia: A Medical Dictionary, Bibliography, and Annotated Research Guide. San Diego, CA: Icon Group International, 2004.

PERIODICALS

Gmyrek, Glenn A., et al. "Bilateral Laparoscopic Adrenalectomy as a Treatment for Classic Congenital Adrenal Hyperplasia Attributable to 21-Hydroxylase Deficiency." Pediatrics 109 (February 2002): 28.

ORGANIZATIONS

American Academy of Pediatrics. 141 Northwest Point Blvd., Elk Grove Village, IL 60007–1098. Web site: <www.aap.org/>.

National Adrenal Diseases Foundation. 510 Northern Blvd., Great Neck, NY 11021. Web site: <www.medhelp.org/nadf/>.

WEB SITES

"Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: A Guide for Patients and Their Families." Johns Hopkins Children's Center. Available online at <www.hopkinsmedicine.org/pediatricendocrinology/cah/> (accessed December 8, 2004).

Judith Sims
Jennifer Sisk