congenital adrenal hyperplasia, CYP21A2-related

What Is Congenital Adrenal Hyperplasia, CYP21A2-Related?

Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect the body's adrenal glands. The adrenal glands regulate essential functions in the body, including the production of several important hormones. CAH occurs when the adrenal glands are unable to produce these hormones properly, resulting in a hormone imbalance. CAH, CYP21A2-related is caused by mutations in the CYP21A2 gene. The CYP21A2 gene produces the 21-hydroxylase enzyme. Another name for this disorder is 21-hydroxylase-deficient CAH (21-OHD CAH).

When the 21-hydroxylase enzyme is missing or present at low levels, the adrenal glands are unable to produce two critical hormones, cortisol and aldosterone. The body responds to this deficiency by producing an excess of male sex hormones, called androgens. Collectively, the excess androgen production and hormone deficiencies can lead to a variety of medical problems, which vary in severity depending on the form of CAH. CAH associated with CYP21A2 (21-OHD CAH) has two major forms: classic and non-classic.

Classic Form

The most severe form referred to as classic 21-OHD CAH, can be further divided into two different subtypes: salt wasting and simple virilizing (non-salt wasting) types. The classic salt-wasting type is associated with near-to-complete deficiency of the 21-hydroxylase enzyme, resulting in the complete inability to produce the hormones cortisol and aldosterone. In this type, the body cannot retain enough sodium (salt) and when too much salt is lost in the urine, it may lead to dehydration, vomiting, diarrhea, poor growth, heart-rhythm abnormalities (arrhythmias), and shock (salt wasting). If not properly treated, salt wasting can lead to death in some cases.

Additionally, female newborns often have external genitals that do not clearly appear either male or female (ambiguous genitalia), whereas male newborns may present with enlarged genitals. Signs of early puberty and the exaggerated development of male characteristics (virilization) occur in both males and females with CAH. These symptoms may include: rapid growth and development in early childhood, but shorter-than-average height in adulthood, abnormal menstruation cycles for females, excess facial hair for females, early facial-hair growth for males, severe acne, and infertility in both men and women. Male characteristics such as muscle bulk and a deep voice can occur in females and in boys (masculinization).

The simple virilizing type of CAH is associated with partial 21-hydroxylase deficiency. Unlike the salt-wasting type, individuals with this condition typically do not experience severe and life-threatening sodium-deficiency symptoms as newborns. However, the majority of female newborns with this type will have ambiguous genitalia, and both male and female children may show signs of early puberty.

Non-Classic Form

The non-classic type (late-onset type) is the the least-severe form of 21-OHD CAH and is caused by a mild deficiency of the 21-hydroxylase enzyme. Individuals with this type may start experiencing symptoms related to excess androgen production in childhood, adolescence, or adulthood. Both males and females may exhibit rapid growth in childhood, shorter-than-average stature in adulthood, virilization, and infertility. Additionally, girls may experience symptoms of masculinization and abnormal menstruation. However, some individuals with non-classic CAH may never know they are affected because the symptoms are so mild.

How Common Is Congenital Adrenal Hyperplasia, CYP21A2-Related?

The incidence of 21-OHD CAH varies by type and ethnicity. The incidence for the classic form is approximately 1 in 15,000 births worldwide. The prevalence of the classic form varies from 1 in 300 for Yupik Eskimos in Alaska to 1 in 21,000 in Japanese. The non-classic form of 21-OHD CAH is much more common, with an incidence of approximately 1 in 1000 births. The prevalence of the non-classic form is much higher in some ethnicities, namely in the Ashkenazi Jewish (1 in 27), Hispanic (1 in 40), Slavic (1 in 50), and Italian (1 in 300) ethnicities. Mutations in CYP21A2 account for about 90% of CAH cases.

How Is Congenital Adrenal Hyperplasia, CYP21A2-Related Treated?

Currently, there is no cure for CAH. However, treatments are available to address some of the associated symptoms. Patients benefit from taking hormone-replacement medications, which work to increase levels of deficient hormones and suppress the overproduction of male hormones. Most individuals with classic CAH will need to take hormone medications for the rest of their lives. Those with the less-severe forms of CAH are sometimes able to stop taking these medications in adulthood and are typically treated with lower doses. Some individuals with non-classic CAH do not require any treatment. A multidisciplinary team of physicians, including an endocrinologist, will need to monitor the medication dosage, medication side effects, growth, and sexual development of patients who continue to receive treatment.

Newborn females with ambiguous genitalia may need surgery to correct the function and appearance of the external genitalia. Surgery, if needed, is most often performed during infancy, but can be performed later in life. Treatments provided during pregnancy may reduce the degree of virilization in female fetuses. However, because the long-term safety of prenatal treatment is unknown, these therapies are considered experimental and are not recommended by professional guidelines.

What Is the Prognosis for an Individual with Congenital Adrenal Hyperplasia, CYP21A2-Related?

With early diagnosis and proper medication management, most individuals with 21-OHD CAH will have a normal life expectancy. Early death can occur during periods of significant sodium loss (salt crises) if medication dosage is not adequately adjusted, especially during times of illness or trauma. Problems with growth and development, ambiguous genitalia, and virilization are monitored by physicians on an ongoing basis. Females with 21-OHD CAH can become pregnant, but fertility is reduced.