Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia: Definition, Treatment, Symptoms, Diagnosis

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What is congenital adrenal hyperplasia?

Congenital adrenal hyperplasia, also known as CAH, is an inherited disorder affecting the hormones secreted (produced) by the adrenal glands. Approximately 1 in 12,000 infants is affected by CAH. The most common type of CAH is called 21-hydroxylase deficiency which is due to genetic (DNA) changes in the 21-hydroxylase (CYP21A2) gene. The CYP21A2 gene is located on chromosome 6. Children inherit genes from their parents receiving one copy of each gene from their mother (maternal gene) and one copy from their father (paternal gene).

Congenital Adrenal Hyperplasia PatternThe inheritance pattern of CAH is called autosomal recessive (Figure). This means that an affected individual carries DNA changes in both CYP21A2 genes and each parent carries a DNA change on one chromosome. Parents are “carriers” which means that there is a genetic change in the CYP21A2 gene on one chromosome and the other CYP21A2 gene on the other chromosome is normal.

What are the adrenal glands?

The adrenal glands are located just above the kidneys. The adrenal glands consist of two major components. The inner component is the adrenal medulla which secretes a hormone called epinephrine. The outer component is the adrenal cortex. The adrenal cortex makes three hormones: cortisol, aldosterone, and the adrenal androgens.

Cortisol is essential for good health and well-being; it influences blood pressure and glucose levels. Cortisol is very important to the body’s responses to physical stresses such as fever and injury. Aldosterone maintains normal levels of sodium and potassium in the body and influences blood pressure. The adrenal androgens influence the development of pubic hair, axillary hair, and adult type body odor. The adrenal androgens are weak hormones that can be turned into androgens such as testosterone (major hormone made by the testes) or estrogen (one of the major hormones made by the ovaries).

Our bodies regulate the amount of cortisol made by the adrenal gland. When the adrenal gland cannot make enough cortisol, as in CAH, the adrenal gland makes excessive amounts of the adrenal androgens. Some of the signs and symptoms of CAH are due to the excessive amounts of adrenal androgens.

What are the signs and symptoms of CAH?

CAH due to 21-hydroxylase is categorized into two major types, classic and nonclassic, depending on the symptoms. Classic CAH is further classified into salt-losing and simple virilizing forms. In the salt-losing form (also known as the salt-wasting form), the adrenal gland cannot make cortisol or aldosterone. In the simple virilizing form, the adrenal gland can make some aldosterone, but cortisol production is minimal. In the nonclassic form, the adrenal gland can make aldosterone and some cortisol, but there is still not enough cortisol to prevent increased adrenal gland production of the adrenal androgen hormones.

Baby girls with classic CAH often have ambiguous external genitalia. This means that the clitoris is longer than normal and may resemble a penis. The labia may have fused and may resemble male external genitalia. The internal genital structures (such as ovaries, fallopian tubes, and uterus) are normal for female infants. Baby boys with classic CAH have normal male external genital structures including palpable testes in their scrotum.

Although CAH is the most common cause of ambiguous genitalia in female infants, other disorders can also lead to the development of ambiguous genitalia. When infants have ambiguous external genital development, it is sometimes difficult to tell from inspection and examination whether the baby is a girl or a boy. Babies with ambiguous external genitalia need prompt and thorough evaluations by a team of physicians including pediatric endocrinologists, pediatric urologists/pediatric surgeons, and geneticists.

If not promptly diagnosed, the salt-losing form can lead to vomiting, weight loss, dehydration, and possibly, death. To identify infants with classic CAH, all 50 states in the United States and many countries have instituted newborn screening programs. Newborn screening involves collecting a small blood sample during the first few days of life which is analyzed to check for several disorders including CAH.

Some children with CAH appear to be normal at birth. These children may develop pubic hair at earlier than normal ages (less than 8 years for girls and 9 years for boys). In addition to early pubic hair development, symptoms of nonclassic CAH in this age group include premature development of axillary hair and adult type body odor, tall stature, and increased growth rate. Symptoms of nonclassic CAH may not appear until the pubertal or post-pubertal years. During and after puberty, the symptoms of nonclassic CAH in girls include irregular menstrual periods, excessive acne, and excessive hair growth on the face and trunk. After puberty, boys with nonclassic CAH generally do not have any specific symptoms. Newborn screening does not usually identify individuals with nonclassic CAH.

How is CAH diagnosed?

As mentioned above, infant girls with classic CAH are usually identified at birth due to the abnormal appearance of their external genitalia. Most infant boys and some infant girls are detected through newborn screening programs. Newborn screening for CAH involves measurement of a hormone named 17-hydroxyprogesterone. This hormone is often called 17-OHP. When CAH is a possible diagnosis, a blood sample is obtained and a 17-OHP level is measured.

For some infants and for the milder forms of CAH, an ACTH stimulation test might be necessary. This test involves the use of a small dose of synthetic ACTH, given by intravenous infusion or intramuscular injection, which acts on the adrenal gland to promote cortisol production. Synthetic ACTH is similar to the pituitary hormone adrenocorticotropin (ACTH) which normally acts on the adrenal gland. After a short time, a blood sample is obtained to measure a “stimulated” 17-OHP level.

How is CAH treated?

A team approach is used for the treatment of infants, children, adolescents, and adults with CAH. This team includes pediatric endocrinologists, pediatric urologists/surgeons, behavioral health professionals, internal medicine endocrinologists, reproductive endocrinologists, nurse educators, and geneticists. The goal of treatment is to replace the “right” amounts of the missing hormones. Regular visits with your child’s health care professionals are essential to monitor your child’s growth and hormone replacement doses.

Infants with classic forms of CAH should be started on treatment once the diagnosis is confirmed. Treatment includes hormone replacement medications to replace cortisol and aldosterone. Cortisol is often used as the replacement medication. This medication is also called hydrocortisone or Cortef® and is usually administered several times each day. The tablet form of Cortef® is best because this medication does not dissolve consistently in a liquid form. Adolescents and adults who have completed their growth may take hydrocortisone, prednisone, or dexamethasone. Cortisol, prednisone, and dexamethasone are considered to be glucocorticoid hormones. The medication used for aldosterone replacement is called 9α-fludrocortisone acetate or Florinef which is usually given once each day.  Aldosterone is a mineralocorticoid hormone. Over time, medication dosages will need to be adjusted for each individual according to their growth and maturation. Treatment for CAH is for the rest of the individual’s lifetime.

What is stress dosing?

In times of illness, individuals with CAH require increased glucocorticoid doses. Illness and stress are defined as high fever, persistent vomiting and diarrhea, major injuries, or surgical operations. If the affected person cannot take oral medications, the glucocorticoid dose must be given by injection. Solu-Cortef® is one form of injectable hydrocortisone that is commonly used. Parents and older individuals with CAH need to learn how to administer injectable hydrocortisone. Individuals with CAH need to wear a Medic-Alert ID badge. Stress dosing is not necessary for upper respiratory tract infections without fever, uncomplicated cuts and bruises, or psychological stress. When in doubt about the need for stress dosing, the patient’s health care provider should be contacted immediately.

My infant daughter has ambiguous external genitalia and was just diagnosed to have CAH. What’s next?

Your daughter needs to be evaluated and treated by a team of health care professionals including pediatric endocrinologists, pediatric urologists/pediatric surgeons, behavioral health professionals, nurse educators, and geneticists. If not already obtained, confirmatory blood work will need to be checked. She will need to be started promptly on appropriate hormone replacement therapy. Some infants may require additional salt supplementation.  All medications especially salt supplementation and medication adjustments should be made by your child’s physicians. You will need to learn about stress dosing and how to administer injectable hydrocortisone (Solu-Cortef®) by intramuscular injection.

How will my daughter’s ambiguous external genitalia be treated?

Some girls with ambiguous genitalia associated with CAH benefit from feminizing genital surgery. Only an experienced pediatric urologist/surgeon should evaluate your daughter to determine if she would benefit from this surgical procedure. And, only an experienced pediatric urologist/surgeon should perform this surgery. The surgical procedure should be performed in a center with experienced pediatric endocrinologists and support staff. Generally, this surgical procedure is performed during the first year of life. Most infants recover within a few days.

Will my child with CAH be able to have children?

Girls and boys with CAH need to follow their physicians’ recommendations regarding hormone replacement therapy. A girl with CAH has normal ovaries, fallopian tubes, and uterus. Young adults with CAH are generally able to have children.

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