Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is caused by changes (mutations) in the CYP21A2 gene. This gene provides instructions for making an enzyme called 21-hydroxylase, which is found in the adrenal glands. The adrenal glands are cone-shaped organs that sit on top of the kidneys and are responsible for releasing various types of hormones that the body needs to function. Mutations in CYP21A2 lead to deficient levels of 21-hydroxylase which cause low levels of hormones such as cortisol and/or aldosterone and an overproduction of androgens (male hormones such as testosterone). Cortisol is a hormone that affects energy levels, blood sugar levels, blood pressure, and the body's response to stress, illness, and injury. Aldosterone helps the body maintain the proper level of sodium (salt) and water and helps maintain blood pressure. Irregular levels of these hormones lead to the signs and symptoms of NCAH.

The amount of functional 21-hydroxylase enzyme determines the severity of the disorder. People with NCAH have CYP21A2 mutations that result in the production of reduced amounts of the enzyme, but more enzyme than the classic form of congenital adrenal hyperplasia.

Babies born in the USA are screened at birth through newborn screening for the classic salt wasting and simple virilizing forms of 21-hydroxylase deficiency. For babies that test positive on the newborn screen for this disorder, additional biochemical and genetic testing is done to confirm the diagnosis. The less severe, non-classical form of 21-hydroxylase def is diagnosed based on the clinical symptoms, biochemical testing to look for excess hormone production. Genetic testing may also be helpful to determine the type and severity of 21-hydroxylase deficiency.

A diagnosis of non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is often suspected based on the presence of characteristic signs and symptoms. Additional testing can then be ordered to confirm the diagnosis. This may include a blood test to measure the concentration of 17-hydroxyprogesterone (17-OHP) and/or an adrenocorticotropic hormone (ACTH) stimulation test. An ACTH stimulation test involves measuring the concentration of 17-OHP in the blood before ACTH is administered and 60 min after ACTH is given.

21-hydroxylase deficiency is inherited in an autosomal recessive pattern. All individuals inherit two copies of each gene. To have 21-hydroxylase deficiency, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

People with autosomal recessive conditions inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disorder typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a:

25% (1 in 4) chance to have the disorder

50% (1 in 2) chance to be an unaffected carrier like each parent

25% (1 in 4) chance to be unaffected and not be a carrier

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

The long-term outlook (prognosis) for people with non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is generally good. NCAH is usually not life-threatening and is relatively mild compared to classic congenital adrenal hyperplasia. Some women may have no signs or symptoms of the condition while others may require treatment for hirsutism, infertility or other health problems. Little has been published about males with NCAH. They may have early beard growth and relatively small testes. Typically, they have normal sperm counts.

The long-term outlook for people with 21-hydroxylase deficiency is dependent on the severity of the symptoms, the response to medications and the presence of any other medical conditions. In general, with early diagnosis and continuous lifetime treatment, the long-term outlook for people with this disorder is good. Long term complications of this condition may include fertility and mental health issues.

Approximately 1 in 10 to 15,000 people in the United States has congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency. The prevalence is higher is other parts of the world.

In some cases, people affected by non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) may not require any treatment. Many are asymptomatic throughout their lives, although symptoms may develop during puberty, after puberty, or post partum. If symptoms are present, a glucocorticoid called dexamethasone is often recommended. Dexamethasone can treat irregular menstruation, acne, and excess body hair (hirsutism).

Treatment for 21-hydroxylase deficiency depends on the severity of symptoms and the form of the condition. The goals of treatment are to manage to symptoms. Infants identified at birth with 21-hydroxylase deficiency are treated with hormones and steroids to prevent a salt-wasting crisis. In childhood and adulthood, other medications may be used to improve growth and fertility. Males should be monitored for the growth of testicular adrenal rest tumors, a benign tumor that can cause infertility. In some cases, females with ambiguous genitalia may be offered surgical correction. Some people with this condition have psychological issues and may benefit from therapy.

At least one organization has published clinical practice guidelines for 21-hydroxylase deficiency.

Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provides information related to the health of children, adults, and families. Click on the link to view information on this topic.

The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.