21-Hydroxylase Deficiency

What is 21-Hydroxylase Deficiency?

Congenital Adrenal Hyperplasia (CAH) is a genetic disorder that happens when the adrenal glands lack certain enzymes needed to make a hormone called cortisol. The most common cause of this condition is a deficiency in a specific enzyme known as 21-hydroxylase, which accounts for over 90% of all CAH cases. The treatment mainly involves replacing the missing hormones.

Diagnosing and treating this condition before birth is crucial, especially in baby girls, to prevent abnormal development of the genitals. Unfortunately, boys with this enzyme deficiency often get diagnosed late when they show severe symptoms relating to insufficient adrenal hormones. Therefore, newborn screening programs that measure a hormone called 17-hydroxyprogesterone are now common in all US states and many other countries. These tests help to detect most babies with severe CAH and some with a milder form of the condition.

However, while it’s rare for these tests to miss a case (false negatives), they sometimes indicate a positive result where none exists (false positives), particularly in premature babies. For these babies, it’s recommended to measure this hormone periodically. If a baby’s screening test comes back positive for CAH, a second blood sample should be taken to confirm the result, along with measures of the baby’s blood salt levels.

The information here seeks to emphasize the importance of recognizing and treating 21-hydroxylase deficiency.

What Causes 21-Hydroxylase Deficiency?

CAH, or Congenital Adrenal Hyperplasia, is a genetic disorder that you can only have if both of your parents carry the gene for it. This disorder affects an enzyme called 21-hydroxylase that helps control how our bodies work.

This enzyme, also known as cytochrome p450c21, is found in the endoplasmic reticulum, a structure inside our cells. There are two CYP21 genes related to this enzyme, positioned on the number 6 chromosome. One of these genes is actually functional, while the other one is just a pseudogene, serving no real purpose. Most of the genetic mutations that cause the depletion of 21-hydroxylase are a result of an interaction between these two genes.

There are many different types of mutations that can interfere with these genes. Some mutations completely stop the production of the enzyme, while others only partially affect it. There is a connection between the seriousness of the disease and the type of mutations involved. For example, people who suffer from a severe form of the condition, known as salt-wasting disease, often have gene mutations that completely stop the enzyme’s activity.

Sometimes, patients may have two different types of mutations, with one gene being more seriously affected than the other; in these cases, the severity of the disease largely depends on the gene that is less affected.

Genetic testing can identify changes and deletion mutations in the CYP21 gene. This can help detect up to 95% of individuals affected by this disease.

Risk Factors and Frequency for 21-Hydroxylase Deficiency

Congenital adrenal hyperplasia is a condition that affects people of all races across the globe. The more severe form, known as classical 21-hydroxylase-deficient CAH, affects about 1 in 15,000 to 20,000 newborns. Of these, around 70% have the type that affects the body’s salt balance, while 30% have a form that simply causes visible changes.

The less severe variant, called nonclassic congenital adrenal hyperplasia, is quite common and affects about 1 in 1000 people in the general population. However, it’s more common in certain ethnic groups like Ashkenazi Jews and Hispanics.

Signs and Symptoms of 21-Hydroxylase Deficiency

The classic deficiency of 21-Hydroxylase has three forms: Salt-wasting, Simple Virilizing, and Non-classic 21-Hydroxylase Deficiency forms.

• Salt-wasting form: This is the most severe form found in roughly 75% of patients. It involves the inability to produce two vital hormones – cortisol and aldosterone. The symptoms include ambiguous genitalia in infant females, and in males, non-specific symptoms such as vomiting, dehydration, and poor feeding between the ages of 1 to 3 weeks. Due to the lack of aldosterone, patients with this form constantly excrete salt, leading to low blood volume and a condition called hyperreninemia. Patients may experience high levels of potassium in the blood, especially during infancy. The lack of cortisol may lead to poor heart function, low response to stress hormones, reduced kidney function, and increased secretion of anti-diuretic hormone. Females are exposed to high levels of adrenal sex hormones, leading to ambiguous genitalia at birth and potential long-term health issues if left untreated.
• Simple Virilizing form: This form is found in roughly 25% of patients but allows normal aldosterone biosynthesis. The symptoms include ambiguous genitalia in females at birth. In males, diagnosis can happen in childhood when signs of excess androgen develop. This form occurs when there are mutations leading to amino acid substitutions that allow the production of aldosterone, but decrease levels of cortisol.
• Non-classic 21-Hydroxylase Deficiency form: This is the mild form and most common, seen in 0.1% to 0.2% of the general white population and 1% to 2% among Ashkenazi Jews. This form allows normal levels of cortisol and aldosterone, but there’s mild to moderate overproduction of sex hormones precursors. Females may present symptoms at any age but usually not younger than 6 months. The most common symptom at presentation is abnormal hair growth, and menstrual irregularities and acne may also exist. Thus, it can be easily confused with a condition called polycystic ovarian syndrome.

Testing for 21-Hydroxylase Deficiency

When it comes to the screening process for certain medical issues, there are several important steps. First, newborn screening programs can check for a condition known as 21-hydroxylase deficiency. Also, a hormone called 17-hydroxyprogesterone will typically be very high (usually above 1000 ng/dL) in someone with the classic form of a particular condition.

Next, tests for the levels of potassium and sodium in the blood (known as hyperkalemia and hyponatremia respectively) are performed, as well as checking the amounts of a hormone called aldosterone and something called plasma renin activity. These tests, especially the ratio of plasma renin activity to aldosterone, can provide clues about whether the body is having trouble making mineralocorticoids, which are hormones that help control the amount of sodium and potassium in your blood.

Another important part of the screening process is the ACTH stimulation test. This involves giving the patient a small dose of a man-made version of ACTH, a hormone that signals your adrenal glands to release other hormones. This test can help doctors understand how well the adrenal glands are working and pinpoint possible issues.

In this test, a full adrenal profile is taken before and 60 minutes after the ACTH is given. This profile tests the levels of a variety of hormones to give a thorough view of adrenal function. Doctors will check the results using a special chart called a nomogram.

If a baby is showing signs of ambiguous genitalia, meaning it’s unclear if the baby is male or female, a test known as a karyotype may be done to decide the baby’s chromosomal sex. Additionally, an ultrasound of the pelvic region should be carried out to look for the presence of a uterus or any related kidney problems.

A bone age study might be suggested if a patient is showing early signs of puberty, such as pubic hair growth. Moreover, if a patient is showing signs of sudden adrenal failure, a type of imaging called a CT scan can be carried out on the adrenal glands to rule out the possibility of a hemorrhage. Lastly, a procedure called urogenitography is done to get a detailed view of the internal genitalia’s structure.

Treatment Options for 21-Hydroxylase Deficiency

An ‘acute adrenal crisis’ is a medical emergency. The first step in care is to immediately start hydration with a special type of salt water solution (isotonic sodium chloride), given through an IV. The amount given is generally 20mL/kg, and may need to be given multiple times.

If the patient’s blood sugar levels are too low, they must also be given a glucose solution. Hydrocortisone, a steroid, is very important in treating this condition and should be given as soon as possible, alongside the IV fluids.

More severe cases may require additional treatments. This includes direct IV access into major blood vessels, medications to raise blood pressure, and a higher concentration of glucose. Too much potassium in the blood, which can be dangerous, may also need extra therapy, including a substance that reduces potassium levels, IV calcium, insulin, and bicarbonate.

Newborn babies are routinely tested for a condition related to the adrenal glands called ‘CAH’ in all US states and around 40 other countries. If a test comes back positive for CAH in a baby, it needs to be double checked by testing another blood sample. If CAH is suspected, the baby should be started on important treatments, specifically glucocorticoid and mineralocorticoid, to prevent serious medical emergencies.

The main goal of long-term care is to control the over-production of androgen by providing the body with the hormones it lacks. The appropriate treatment can prevent medical emergencies, abnormal physical changes, and enable normal growth, maturity, sex life, and fertility.

Hydrocortisone is usually given orally with a split dose of 10 to 20 mg/m2 each day to replace missing cortisol. The medication helps control the overproduction of adrenal androgens. It’s the preferred choice due to its shorter half-life and the fact it has a minimal effect on growth. The treatment’s efficacy can be monitored using several hormonal measures.

Once children grow older and finish growing, they can transition to other medications such as prednisone or dexamethasone.

Babies with a specific form of CAH that causes difficulty maintaining salt levels will need replacement with mineralocorticoids – typically fludrocortisone and sodium chloride.

Newborns with unusual sexual characteristics should receive a surgical evaluation. If required, corrective surgery could be planned. Parents should be properly informed about the risks and rewards of surgery. Surgery is typically carried out before the first year of age for severely affected female babies. Extreme cases might require removing the adrenal glands, especially for adult women with CAH who struggle with fertility. However, the risk of patients not complying with treatment should be considered before taking this step.

What else can 21-Hydroxylase Deficiency be?

• Conditions that occur due to a deficiency in 11-beta-hydroxylase and 3 beta-hydroxysteroid dehydrogenase
• Five-alpha-reductase deficiency (a condition that affects male sexual development)
• Adrenal hypoplasia (not enough hormone-producing tissue in the adrenal glands)
• Adrenal insufficiency (the adrenal glands can’t produce enough hormones)
• Androgen insensitivity syndrome (a male-born person is resistant to male hormones)
• Bilateral adrenal hemorrhage (bleeding in both adrenal glands)
• Other causes for high levels of potassium and low levels of sodium in the blood
• Hypertrophic pyloric stenosis (a thickening of the stomach muscles that prevents food from passing into the intestines)
• Obstructive uropathy (a blocked urine flow)
• Polycystic ovarian syndrome (a hormone disorder causing larger ovaries with small cysts on the outer edges)
• Problems in the synthesis of the male hormone testosterone
• Denys-Drash syndrome (a rare disorder affecting the kidneys and reproductive system)
• Disorders of gender development
• Familial glucocorticoid deficiency (a rare disease where the adrenal gland doesn’t produce enough of certain hormones)

What to expect with 21-Hydroxylase Deficiency

Children with a condition called Congenital Adrenal Hyperplasia (CAH) often grow tall in their early years but end up shorter than average in adulthood. Recent studies show these patients are usually around 10 cm shorter than their predicted height, based on their parents’ heights. This difference is primarily due to excess androgen hormones causing early bone growth and puberty in these children. Additionally, the treatment for CAH, which involves some steroids, could suppress growth and result in a smaller final height. Some newer treatments using growth hormones are showing promising results, with an average height gain of 7.3 cm.

There’s ongoing debate about the impact of high levels of sex hormones during pregnancy on personality later in life. However, there’s consistent evidence showing that these hormones affect the types of play activities children prefer.

Most children with CAH develop normally from a psychological standpoint. Notably, regardless of tendencies towards male behavior and fantasies, most girls with this condition identify as females and are heterosexual. People with CAH can have children, though their fertility rates are generally lower due to a combination of biological, psychological, social, and sexual factors.

Most patients with CAH have normal bone density. But many also have metabolic problems like obesity, insulin resistance, high cholesterol, and a condition called polycystic ovarian syndrome. These can either be due to the condition itself or the steroids used in its treatment.

Managing this disease and its long-term effects can be complex for medical professionals. It often requires a team of specialists to provide the best care. Future treatments, like gene therapy, have potential to offer a cure for CAH.

Possible Complications When Diagnosed with 21-Hydroxylase Deficiency

Complications are quite common in people with congenital adrenal hyperplasia. These complications depend on the levels of certain hormones, known as glucocorticoids, in the patient’s body. If the patient isn’t getting enough glucocorticoids, they could develop adrenal insufficiency and further virilization in the so-called virilizing forms. On the other hand, if the patient is getting too much glucocorticoids, they could develop growth failure, becoming overweight, stretch marks, high blood pressure, high blood sugar, and cataracts.

When a patient is given an excess of mineralocorticoids, these can lead to high blood pressure and low levels of potassium in the blood (hypokalemia). If the patient has a deficiency in another hormone called aldosterone, this can lead to salt wasting, which in turn can result in failure to thrive, low blood volume, and shock.

Complications in a nutshell:

• Adrenal insufficiency and virilization with low glucocorticoid levels
• Growth failure, obesity, stretch marks, hypertension, hyperglycemia, and cataracts with high glucocorticoid levels
• Hypertension and hypokalemia with excess mineralocorticoid
• Salt wasting, failure to thrive, hypovolemia, and shock with aldosterone deficiency

Preventing 21-Hydroxylase Deficiency

It is crucial that patients suffering from this disease, and their families, are educated about the correct treatment methods. Especially, following the prescribed medical therapy is of utmost importance. Too little or too much use of glucocorticosteroids can severely impact the patients’ growth and well-being. Whether it’s the caregivers or the patients themselves as they age, everyone needs to understand how to manage the treatment correctly and know when it’s necessary to seek professional medical help.