21-hydroxylase-deficient congenital adrenal hyperplasia
What is 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia?
Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect the body’s adrenal glands. The adrenal glands are located above each kidney and 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.
More than 90% of of CAH cases are caused by deficiency of the 21-hydroxylase enzyme. When this 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.
There are two major forms of 21-hydroxylase-deficient CAH: classic CAH and non-classic CAH.
The most severe form, referred to as classic CAH, can be divided into two different subtypes: the salt-wasting type and the simple virilizing type (non salt-wasting type). The classic salt-wasting type is associated with near to complete deficiency of the enzyme, 21-hydroxylase, resulting in the complete inability to produce the hormones, cortisol and aldosterone. In this type, the body cannot retain enough sodium (salt). When too much salt is lost in the urine, it may lead to dehydration, vomiting, diarrhea, failure to thrive, heart rhythm abnormalities (arrhythmias), and shock; if not properly treated, death may occur in some cases. In addition, female newborns often have external genitalia that do not clearly appear either male or female (ambiguous genitalia), whereas male newborns may present with enlarged genitalia. Signs of early puberty (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.
The simple virilizing type of CAH is associated with partial 21-hydroxylase deficiency. Unlike the salt-wasting type, these individuals 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.
The non-classic type (late-onset type) is the the least severe form of CAH and is caused by 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 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia?
The incidence of CAH varies by type and is more prevalent in certain ethnicities. Classic CAH occurs in approximately 1 in 15,000 births worldwide, while non-classic CAH is much more common, occurring in approximately 1 in 1,000 births. In some populations, namely individuals of Ashkenazi Jewish, Hispanic, Italian, and Yugoslav descent, the prevalence of the non-classic CAH can reach as high as 3-4 percent.
How is 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia 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 people with classic CAH will need to take hormone medications for the rest of their life. 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 a person with 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia?
With early diagnosis and proper medication management, most individuals with 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, infertility, ambiguous genitalia, and virilization are monitored by physicians on an ongoing basis.