What is Congenital Adrenal Hyperplasia?

Congenital adrenal hyperplia (CAH) is a genetic disease that occurs when there are changes in the genes that control enzymes responsible for creating important body chemicals from cholesterol in the adrenal glands. These chemicals include substances that manage stress, maintain blood pressure and salt balance, and develop sexual features. In many cases, the disease results in either too much or too little production of sex-related hormones, which can affect the sexual development of infants, children, or adults. In some cases, these changes can also cause a severe loss of salt from the body, which can increase health risks in newborns. To help identify and start treatment for this disease early, newborns are usually screened for CAH in the United States and many developed countries. This regular screening is strongly recommended.

What Causes Congenital Adrenal Hyperplasia?

Congenital adrenal hyperplasia, often called CAH, usually happens because of changes or deletions in a gene called CYP21A. This results in a deficiency of an enzyme called 21-hydroxylase, which is found in 90-95% of CAH cases. Changes that affect CYP21A are also quite common.

Generally, about one in every 60 people in the population has CAH. However, in certain smaller, genetically isolated groups, the rate can be as high as one in three. CAH can be found in every population, though the deficiency of a different enzyme, 11-beta-hydroxylase, is more common in people of Iranian, Jewish, or Moroccan descent.

The severity of the disease and how it appears can vary a lot. This depends on the location and extent of gene changes or deletions, and can cause complicated variations. There are almost 300 known variations of the CYP21A2 gene for instance, so it can be quite challenging to determine exactly what’s going on genetically for each person suffering from CAH.

There are different forms of CAH as well. For example, classic CAH can show up as either simple virilizing CAH or salt-wasting CAH and it’s usually diagnosed in infancy. Nonclassic CAH patients might not show any symptoms. Alternatively, they might develop a milder form of virilization, which means they show physical traits typically associated with male bodies, after they are born.

Risk Factors and Frequency for Congenital Adrenal Hyperplasia

In the United States, a condition called congenital adrenal hyperplasia is more often seen in Native Americans and Yupik Eskimos. Among Caucasian individuals, the occurrence is roughly 1 in 15,000.

This condition can affect both males and females equally, as it is inherited in a way that doesn’t favor one sex over the other. However, the existing levels of certain hormones like testosterone can affect how the condition appears in each gender. Symptoms of this condition are typically noticeable at birth or shortly afterwards. These can include unclear genitalia, early signs of masculinity, or excessive loss of salt. When the case is less typical, it may be identified around the time of puberty. Females may show signs of virilization or have irregular menstrual cycles.

Signs and Symptoms of Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia is a condition that affects both males and females and can present with various symptoms depending on whether there is inadequate production of a substance called mineralocorticoids and an excess of substances called androgens.

When there is not enough mineralocorticoids, individuals may experience:

  • Vomiting which can result in dehydration, low blood volume (hypovolemia), shock and ultimately lead to death due to a condition known as salt-wasting

However, when there are too many androgens, symptoms may appear as follows:

  • In males, it can cause excessive facial hair, normal sized penis with unusual virilization but no sperm
  • Females may have unclear sexual features (ambiguous genitalia), irregular periods, difficulty getting pregnant due to lack of ovulation, an enlarged clitoris, and a shallow vagina
  • Both genders might experience early pubic hair and rapid growth during childhood, and either too early onset of puberty or failure for puberty to occur

In some cases, under-virilization can occur in males (XY), which can result in female external genitalia. In females, inadequate sexual hormone (hypogonadism) can cause underdeveloped sexual features (sexual infantilism), abnormal puberty development and infertility.

Testing for Congenital Adrenal Hyperplasia

Due to high levels of a hormone called androgens in the womb, newborn baby girls can sometimes have unclear physical features of their genitals. A condition known as ‘congenital adrenal hyperplasia due to 21-hydroxylase deficiency’ is a common cause of this. Girls with a less severe form of this condition may start to develop pubic hair earlier than normal. In the case of young women, this condition can lead to fewer periods than normal, cysts on their ovaries, and hair growth in areas it usually doesn’t grow in women, like the face and body (like polycystic ovary syndrome).

Most baby boys with this condition won’t show any signs at birth. However, in some cases, it could lead to darker skin and penis enlargement, while those with a form of the condition called ‘salt-wasting disease’ can lead to low sodium levels and low blood volume. Boys with a form of the condition that doesn’t lead to salt-wasting disease will start to show signs of male characteristic development at an early age. In rare forms of the condition, boys will have less male characteristics than normal.

To diagnose congenital adrenal hyperplasia, a two-step approach is used. The first step involves doing a blood test to measure a hormone called 17OHP, which helps to confirm a 21-hydroxylase deficiency. If the levels are high, the test is repeated. If classic 21-hydroxylase deficiency is present, the levels will be higher than 242 nmol/L.

Newborn screening programs for this condition are prevalent worldwide, with specific criteria for babies across different weight and gestational age brackets. Higher levels of this hormone can be found in unhealthy, stressed, or premature babies who do not have congenital adrenal hyperplasia. Therefore, babies that are diagnosed early can start their treatment at a young age and maintain a relatively normal life.

A more technical test called ‘liquid chromatography-tandem mass spectrometry’ can help diagnose congenital adrenal hyperplasia due to defects in other enzymes such as 11-beta-hydroxylase. When necessary, a test known as a ‘cosyntropin stimulation test’ is then conducted followed by a complete adrenocortical profile to further assess the condition.

If children show clear clinical signs of 21-hydroxylase deficiency, labs might perform other tests like genetic analysis – even though it’s not needed always. However, some lab reports might note symptoms like low blood glucose due to low cortisol hormone, low sodium levels due to low aldosterone hormone, high potassium levels due to low aldosterone hormone, and elevated 17alpha-hydroxylase hormones.

In general, imaging tests aren’t required to diagnose this condition unless there’s suspicion of bleeding in the adrenal glands. However, when the gender of a baby is unclear due to this condition, doctors might recommend an ultrasound to check the anatomy of the baby’s urogenital tract for any abnormalities.

Sometimes, a chromosomal study is done for babies born with unclear genitals to identify the gender. In some cases, genetic testing is also done during pregnancy to counsel the mother.
In some centers, babies are routinely screened for this condition to prevent the development of a life-threatening salt-wasting crisis.

Treatment Options for Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a genetic condition, inherited when both parents carry the gene. In rare cases, it can be prevented through preimplantation genetic diagnosis, but this is complex and not always successful. The goals of treatment for CAH vary depending on the age of the patient.

For infants and children, the treatment objectives revolve around preventing crises linked to the adrenal gland, avoiding the early onset of male sex characteristics, promoting normal growth, and avoiding the imbalance of electrolytes and dehydration. As patients grow into teenagers and adults, the focus of treatment expands to also cover maintaining regular reproductive capabilities and fertility, while avoiding chronic medication-related complications, including Cushing syndrome, a condition that results from high levels of a stress hormone called cortisol. Success in achieving these goals often requires close monitoring and education about the condition’s signs, symptoms, and treatments. Patients with CAH are usually advised to wear medical identification and have an emergency injection kit containing glucocorticoid, a type of steroid hormone.

Broadly, the general principles for treating CAH include:

– Providing enough glucocorticoids to decrease overproduction of sex hormones and mineralocorticoids, hormones that balance salt and water in the body.
– Replacing mineralocorticoids and extra salt if needed.
– Administering replacement testosterone or estrogen during puberty if lacking.
– Offering additional therapies as required to optimize growth by delaying puberty or slowing bone maturation.

Medical professionals avoid using spironolactone, a medication that helps the body rid itself of excess salt, in those affected by salt-wasting CAH due to the increased risk for dehydration. Patients with CAH may also need extra doses of steroids to manage situations with high stress, such as severe trauma, surgery, or certain illnesses, but not for minor conditions, everyday stress, or exercise.

In terms of surgical treatments, only a select group of infants with severe forms of virilization or ambiguous genitalia might require surgery, typically recommended only after comprehensive consultations with a team of specialized doctors. This surgery should happen at centers that specialize in genitoplasty and only conducted by experienced surgeons.

Finally, individuals with CAH require lifelong monitoring to keep a check on the doses and side effects of their hormone treatments. Regular screening for cardiovascular and metabolic diseases is also strongly recommended, in line with screenings suggested for the general population.

When diagnosing congenital adrenal hyperplasia, a condition that affects the adrenal glands, doctors consider several other conditions that can cause similar symptoms. These include:

  • Adrenal hypoplasia (underdevelopment of the adrenal glands)
  • Androgen insensitivity syndrome (a condition where the body can’t respond properly to male sex hormones)
  • Bilateral Adrenal Hemorrhage (bleeding into both adrenal glands)
  • Defects in testosterone synthesis (problems with the creation of the male sex hormone)
  • Denys-Drash syndrome (a rare disorder that affects the kidneys and sexual development)
  • Disorders of sex development (conditions where development of chromosomal, gonadal, or anatomical sex is atypical)
  • Familial glucocorticoid deficiency (an inherited disorder that affects the adrenal glands)
  • Fluid and electrolyte issues (problems with body’s water and minerals)

These conditions must be carefully considered and appropriate tests conducted to ensure an accurate diagnosis.

What to expect with Congenital Adrenal Hyperplasia

If the condition is quickly identified and treated, most patients will have a good outlook. However, overcoming the physical symptoms doesn’t necessarily mean emotional troubles are resolved. Many patients face long-term emotional struggles due to the disorder’s effects on their genital appearance.

Other problems these patients may experience include:

* Difficulty conceiving a child
* Being relatively short in height
* Issues with identifying as a female
* Problems related to the development of male features in women
* Risk of early death if they aren’t given certain medications (stress doses of corticosteroids/glucocorticoids) during major surgery, trauma, or illness.

Possible Complications When Diagnosed with Congenital Adrenal Hyperplasia

Hormonal imbalances can lead to several problems that manifest in different ways. Here are some common complications that can occur:

  • Failure in growth
  • Obesity
  • High blood pressure (Hypertension)
  • Excessive levels of sugar in the blood (Hyperglycemia)
  • Cataracts, a clouding of the eye’s lens
  • Infertility, which is the inability to conceive a child
  • Masses in the sexual and adrenal glands
  • Repeated urinary tract infections and blockage of menstruation in women with extreme masculine physical traits who haven’t had surgery in their childhood.

Preventing Congenital Adrenal Hyperplasia

People with congenital adrenal hyperplasia and their families need to learn about the condition to understand why they need hormone replacement therapy. This therapy is necessary because they have fewer hormones than normal. They also need to know that during periods of sickness or stress, they’ll need more glucocorticoids, a type of hormone. Additionally, they need to be taught how to inject these glucocorticoids into muscles themselves.

Frequently asked questions

Congenital Adrenal Hyperplasia (CAH) is a genetic disease that occurs when there are changes in the genes that control enzymes responsible for creating important body chemicals from cholesterol in the adrenal glands.

Congenital Adrenal Hyperplasia is generally found in about one in every 60 people in the population.

Signs and symptoms of Congenital Adrenal Hyperplasia include: - Inadequate production of mineralocorticoids: - Vomiting, which can lead to dehydration, hypovolemia, shock, and potentially death due to salt-wasting. - Excess production of androgens: - In males: - Excessive facial hair. - Normal sized penis with unusual virilization but no sperm. - In females: - Unclear sexual features (ambiguous genitalia). - Irregular periods. - Difficulty getting pregnant due to lack of ovulation. - Enlarged clitoris. - Shallow vagina. - Both genders: - Early pubic hair and rapid growth during childhood. - Either too early onset of puberty or failure for puberty to occur. - Under-virilization in males (XY): - Female external genitalia. - Inadequate sexual hormone (hypogonadism) in females: - Underdeveloped sexual features (sexual infantilism). - Abnormal puberty development. - Infertility.

Congenital Adrenal Hyperplasia usually happens because of changes or deletions in a gene called CYP21A.

The doctor needs to rule out the following conditions when diagnosing Congenital Adrenal Hyperplasia: - Adrenal hypoplasia (underdevelopment of the adrenal glands) - Androgen insensitivity syndrome (a condition where the body can't respond properly to male sex hormones) - Bilateral Adrenal Hemorrhage (bleeding into both adrenal glands) - Defects in testosterone synthesis (problems with the creation of the male sex hormone) - Denys-Drash syndrome (a rare disorder that affects the kidneys and sexual development) - Disorders of sex development (conditions where development of chromosomal, gonadal, or anatomical sex is atypical) - Familial glucocorticoid deficiency (an inherited disorder that affects the adrenal glands) - Fluid and electrolyte issues (problems with body's water and minerals)

The types of tests needed for Congenital Adrenal Hyperplasia include: 1. Blood test to measure the hormone 17OHP to confirm a 21-hydroxylase deficiency. If levels are high, the test is repeated. Levels higher than 242 nmol/L indicate classic 21-hydroxylase deficiency. 2. Newborn screening programs that use specific criteria for babies of different weight and gestational age brackets. 3. Liquid chromatography-tandem mass spectrometry to diagnose CAH due to defects in other enzymes. 4. Cosyntropin stimulation test followed by a complete adrenocortical profile to further assess the condition. 5. Genetic analysis, if necessary, to confirm the diagnosis. 6. Imaging tests, such as ultrasound, may be recommended to check the anatomy of the urogenital tract for abnormalities. 7. Chromosomal study for babies with unclear genitals to identify gender. 8. Genetic testing during pregnancy for counseling the mother. 9. Regular monitoring and screening for cardiovascular and metabolic diseases, as well as monitoring of hormone treatments and side effects.

Congenital Adrenal Hyperplasia (CAH) is treated by providing enough glucocorticoids to decrease the overproduction of sex hormones and mineralocorticoids, replacing mineralocorticoids and extra salt if needed, administering replacement testosterone or estrogen during puberty if lacking, and offering additional therapies as required to optimize growth by delaying puberty or slowing bone maturation. Surgical treatments are only recommended for a select group of infants with severe forms of virilization or ambiguous genitalia, and should be conducted by experienced surgeons at specialized centers. Lifelong monitoring and regular screening for cardiovascular and metabolic diseases are also strongly recommended.

The side effects when treating Congenital Adrenal Hyperplasia (CAH) can include: - Failure in growth - Obesity - High blood pressure (Hypertension) - Excessive levels of sugar in the blood (Hyperglycemia) - Cataracts, a clouding of the eye's lens - Infertility, which is the inability to conceive a child - Masses in the sexual and adrenal glands - Repeated urinary tract infections and blockage of menstruation in women with extreme masculine physical traits who haven't had surgery in their childhood.

If the condition is quickly identified and treated, most patients will have a good outlook. However, overcoming the physical symptoms doesn't necessarily mean emotional troubles are resolved. Many patients face long-term emotional struggles due to the disorder's effects on their genital appearance. Other problems these patients may experience include difficulty conceiving a child, being relatively short in height, issues with identifying as a female, problems related to the development of male features in women, and a risk of early death if they aren't given certain medications (stress doses of corticosteroids/glucocorticoids) during major surgery, trauma, or illness.

An endocrinologist.

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