Alternative Names
Adrenogenital Syndrome; Congenital Adrenal Hyperplasia; Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency
Symptoms & Characteristics
Congenital adrenal hyperplasia (CAH) refers to a group of genetic conditions that affect the adrenal glands. The adrenal glands are located on top of the kidneys and produce different hormones that regulate many functions in the body.
21-hydroxylase deficiency is the most common form of CAH and is caused by a deficiency of the enzyme 21-hydroxylase. This enzyme is needed to convert cholesterol into the hormones cortisol and aldosterone.
- Cortisol has many functions, such as maintaining blood sugar levels, protecting the body from stress, and suppressing inflammation.
- Aldosterone (sometimes called the salt-retaining hormone) acts on the kidneys to regulate the levels of salt and water in the body, which affects blood pressure.
When the enzyme 21-hydroxylase is deficient, the precursors of cortisol and aldosterone build up in the adrenal glands and are converted to male sex hormones called androgens. Androgens are responsible for the appearance of male secondary sex characteristics (called virilization). Elevated levels of androgens cause male secondary sex characteristics to appear early in males and inappropriately in females.
There are two forms of 21-hydroxylase deficiency, Classic and non-Classic. The Classic form is further subcategorized into two types, Simple virilizing type and Salt-loss type.
Classic forms (features and symptoms are present as birth):
Simple virilizing type occurs when there is potent prenatal androgen exposure. This type accounts for about 25% of affected people.
Common female symptoms include:
- Varying degree of masculinization (development of male characteristics) of external genital organs which is present at birth
- Typically normal internal reproductive organ (uterus, ovaries and fallopian tubes) development
- Abnormal periods or failure to menstruate
- Early appearance of pubic and armpit hair as well as excessive hair growth
Common male symptoms include:
- Males appear normal at birth
- Early puberty (as early as 2-3 years old)
Salt-loss type occurs when there is almost no activity of 21-hydroxylase. In these cases, so little aldosterone is produced that the kidneys do not reabsorb sodium (a component of salt). This can lead to adrenal crises, cardiac problems, dehydration and even death. This type accounts for about 75% of affected people.
non-Classic form (symptom onset after birth):
The levels of functional 21-hydroxylase enzyme are moderate. Both males and females affected with this type can display signs and symptoms of androgen excess after birth. Affected females are not typically virilized at birth.
Management & Treatment
There is no cure for 21-hydroxylase deficiency. However, there is treatment for 21-hydroxylase deficiency, which includes taking a form of cortisol daily and additional doses during times of stress (illness, surgery, etc.). Therefore, early diagnosis and routine surveillance can help to manage some of the symptoms and sometimes prevent related problems.
Classic Forms:
Treatment for CAH principally involves glucocorticoid replacement therapy. For individuals with the salt-wasting form, treatment can involve mineralocorticoid replacement therapy and sodium chloride.
In many states, newborn screening can help identify infants with the classic form of the condition in order to initiate replacement therapy and help prevent crisis.
Glucocorticoid and mineralocorticoid replacement therapy is typically monitored every three to four months while children are actively growing, and less often thereafter. For females who are virilized at birth, surgery to feminize external genitalia and/or vaginal dilation may be performed. Males are typically monitored every three to five years after the onset of puberty for testicular adrenal rest tumors. In adulthood, treatment is aimed at preserving fertility, healthy sexual function, and bone health as well as managing the risk for cardiovascular diseases.
non-Classic Form:
Individuals with non-classic 21-OHD CAH may not always require treatment. Symptoms may sometimes develop during puberty, after puberty, or post partum. In general, affected individuals have been treated with lower amounts of glucocorticoid than those required for individuals with classic forms.
How Common Is It?
The incidence of 21-hydroxylase deficiency varies by type.
- About 1 in 15,000 newborns are believed to be affected with the Classic form.
- About 1 in 100 people are believed to be affected with the non-Classic form.
The prevalence of both the Classic and non-Classic form may vary among certain ethnic groups.
Genetics & Inheritance
21-hydroxylase deficiency is caused by mutations in a gene called CYP21A2, which is located on chromosome 6 at the location p21.3.
- Certain mutations are more common in specific ethnic groups.
We all have two copies of the CYP21A2 gene - one from each parent. In 21-hydroxylase deficiency, it is necessary to have two mutations, one in each gene copy, to be affected. This is called autosomal recessive inheritance.
- Both parents of an affected person are usually obligate carriers (they each have only one mutation). Two carriers have a 25% chance with each pregnancy to have an affected child, but typically do not have symptoms themselves.
There are other genetic conditions that have symptoms and features which overlap with CAH. A genetic consultation with a trained genetic professional is important for a complete evaluation, accurate diagnosis, as well as discussion of the benefits and limitations of testing and recurrence risk.
Genetic Testing
Clinical genetic testing for 21-hydroxylase deficiency can be broken down into two categories: diagnostic testing and carrier testing.
- Diagnostic testing may be used to confirm or rule out a diagnosis in a person suspected to have the disorder. Biochemical testing may also be used for diagnostic purposes, as an elevated concentration of 17-hydroxyprogesterone (17-OHP) is found in affected individuals.
- Carrier testing is typically offered after a clinical diagnosis and/or mutations have already been identified in an affected family member(s). Carrier testing usually involves DNA testing for the known familial mutations or if not available, the most common mutations. Biochemical testing cannot be used for carrier testing purposes.
Carrier testing for the Ashkenazi-specific mutations that cause the non-Classic form of 21-hydroxylase deficiency is available online (over the internet). This testing is available individually or as part of an Ashkenazi Jewish panel. Go to the Tests tab to link to the best providers, compare providers and read provider reviews.
Diagnostic testing and carrier testing for the Classic and non-Classic forms of 21-hydroxylase deficiency for people who are not of Ashkenazi Jewish ancestry is available through an in person genetic consultation for people who are considered at risk. Use our find a genetic professional directory to locate a trained genetic professional in your area.
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