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If you or your child has congenital adrenal hyperplasia (CAH), you’ve probably heard the term “21-hydroxylase deficiency.” This condition involves missing or low levels of 21-hydroxylase — an enzyme (a type of protein) that plays an important role in how the adrenal glands make hormones.
Without enough of this enzyme, the body can’t produce certain hormones needed to regulate salt balance, stress response, and development.
In this article, we’ll explain what 21-hydroxylase deficiency means for people living with CAH. We’ll look at how the enzyme normally works, what happens when it doesn’t, and how this impacts symptoms and diagnosis. We’ll also explore treatment options and share what new research may offer in the future.
As one of the body’s enzymes, 21-hydroxylase acts like a tiny machine with a specific job. Enzymes help carry out many functions in the body by speeding up chemical reactions. They help turn raw materials into useful products. Without enzymes, the body can’t finish making certain substances it needs.
The adrenal glands use 21-hydroxylase to make two important hormones: cortisol and aldosterone. Without this enzyme, the body’s endocrine (hormone) system can’t run smoothly.
The adrenal glands are a pair of small glands that sit right above your kidneys. They impact some of the body’s most important processes, like:
The adrenal glands make different types of hormones, like the following:
Under normal conditions, 21-hydroxylase takes part in a series of steps called hormone pathways. It helps convert a substance called 17-hydroxyprogesterone (17-OHP) into the building blocks for cortisol and aldosterone. When this step happens correctly, the adrenal glands produce enough of these hormones to help keep the body healthy and in balance.
When someone has a 21-hydroxylase deficiency (meaning the enzyme is missing or doesn’t work well), this pathway becomes blocked. As a result, cortisol and aldosterone levels stay too low, and 17-OHP builds up in the body. The body then converts the piled up 17-OHP into excess androgens. This is why people with CAH develop hormone imbalances. This shows why the role of this enzyme is so critical — in a way, it directs traffic inside the adrenal glands and keeps all the hormones moving in balance.
The single most common cause of CAH is 21-hydroxylase deficiency. In fact, it’s found in more than 90 percent of people with this condition. It happens because of mutations (changes) in the CYP21A2 gene. This gene provides the instructions for making the 21-hydroxylase enzyme. When the instructions are faulty, the amount of this enzyme is low or absent.
CAH caused by 21-hydroxylase deficiency is inherited in an autosomal recessive pattern. This means a child must receive one nonworking copy of the gene from each parent to develop the condition. People who carry just one nonworking copy of the gene are called carriers and usually don’t have symptoms.
Without enough enzyme activity, the adrenal glands can’t keep up with the body’s hormonal needs. Too little cortisol and aldosterone can lead to serious health problems, such as salt-wasting. In salt-wasting CAH, the body loses too much sodium through the urine. This can even lead to a life-threatening adrenal crisis — where dangerously low levels of cortisol can cause a lack of blood flow, dehydration, or shock.
The symptoms of 21-hydroxylase deficiency depend on what form of CAH someone has. The two main types are classic and nonclassic.
In classic CAH — which includes the salt-wasting and simple virilizing forms — symptoms often appear in newborns and infants. According to MedlinePlus, female infants may be born with atypical external genitalia, such as a larger clitoris. Babies can develop life-threatening problems from salt loss, such as:
As children grow, excess androgens can cause early puberty, rapid maturation of the growth plates, and a shorter adult height later on. The condition can also cause smaller testes or reduced sperm production.
In the nonclassic form (the mild form), symptoms may not appear until childhood, adolescence, or adulthood. Children with this type of CAH may develop early pubic hair, body odor, or faster growth. In teens and adults, common issues include:
Doctors can diagnose 21-hydroxylase deficiency using a combination of screening tests, blood work, and genetic testing.
In the United States, all newborns are screened for classic 21-hydroxylase deficiency through routine newborn screening. A small blood sample is taken from the heel and tested for 17-OHP. High levels of 17-OHP suggest that 21-hydroxylase isn’t working properly. This test helps catch classic CAH early — often before a baby shows life-threatening symptoms.
If the results of the newborn screen are abnormal, doctors may repeat testing or order an adrenocorticotropic hormone (ACTH) stimulation test to see if the adrenal glands are working properly. In babies with atypical genitalia, a karyotype test may be done. This test looks at the baby’s chromosomes (XX or XY) to establish the genetic sex. A pelvic ultrasound can also check for the presence of a uterus or look for kidney abnormalities.
Imaging tests can also look for changes in the testes. For older children or adults with signs of nonclassic CAH, blood tests after hormone stimulation may confirm the diagnosis.
Genetic testing of the CYP21A2 gene identifies the exact mutations or variants. Knowing a person’s genotype (the details of their gene changes) helps healthcare providers — especially pediatric endocrinologists (specialists in children’s hormones) — better predict how the condition may progress and plan the most effective treatment.
Treatment for 21-hydroxylase deficiency focuses on replacing missing hormones and keeping levels balanced.
In classic CAH, children usually need lifelong treatment with glucocorticoids (a type of steroid hormone). These help replace cortisol and prevent the overproduction of androgens.
Many people with classic CAH — especially those with the salt-wasting form — also need mineralocorticoids to help the body retain salt and maintain healthy blood pressure. Infants and young children may also need salt supplementation in their formula or food.
In nonclassic CAH, treatment depends on signs and symptoms. Some people need only low-dose glucocorticoids to manage specific symptoms. Others may not need daily medication but should still have regular follow-ups with an endocrinologist to monitor hormone levels and watch for changes over time.
Today, treatment for 21-hydroxylase deficiency mostly relies on glucocorticoids, mineralocorticoids, and salt supplements. However, researchers are exploring new therapies that aim to treat the root cause of CAH more directly.
One notable advance is a medication called crinecerfont (Crenessity). This is the first nonsteroidal treatment approved by the U.S. Food and Drug Administration (FDA) for people with CAH. Crinecerfont may help people with classic CAH ages 4 and older maintain better hormone control, allowing for lower doses of glucocorticoids.
On CAHteam, people share their experiences with congenital adrenal hyperplasia, get advice, and find support from others who understand.
Do you or a loved one have a type of CAH caused by 21-hydroxylase deficiency? Let others know in the comments below.
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