Congenital Adrenal Hyperplasia (CAH)

What is CAH?

CAH refers to a group of genetic disorders that affect the adrenal glands. These glands sit on top of the kidneys and release hormones the body needs to function. CAH is caused by three disturbances:

• Too little cortisol (pronounced KAWR-tuh-sawl). The adrenal glands of infants born with CAH cannot make enough of the hormone cortisol. This hormone affects energy levels, blood sugar levels, blood pressure, and the body's response to stress, illness, and injury.
• Too little aldosterone (pronounced al-DOS-tur-own). In about three-fourths of cases, infants born with CAH cannot make enough of the hormone aldosterone, which helps the body maintain the proper level of sodium (salt) and water and helps maintain blood pressure.¹
• Too much androgens (pronounced AN-druh-juhnz or AN-druh-jenz). In certain cases, infants born with CAH produce too much of male hormones, androgens. Proper levels of these hormones are needed for normal growth and development in both boys and girls.

CAH can also cause imbalances in the hormone adrenaline (pronounced uh-DREN-uhl-in), which affects blood sugar levels, blood pressure, and the body's response to stress.^2,3

The hormone imbalance most often seen in CAH cases is too little of a substance called 21-hydroxylase (pronounced hahy-DROK-suh-leys).¹ The adrenal glands need 21-hydroxylase to make proper amounts of hormones. This type of CAH is sometimes referred to as 21-hydroxylase deficiency. In CAH due to 21-hydroxylase deficiency, the adrenal glands cannot make enough cortisol or aldosterone. In addition, the glands make too much androgen. People with 21-hydroxylase deficiency also may not produce enough adrenaline.⁴

A small number of cases of CAH are caused by deficiency in a substance similar to 21-hydroxylase, called 11-hydroxylase.¹ This type of CAH is sometimes referred to as 11-hydroxylase deficiency. In CAH due to 11-hydroxylase deficiency, the adrenal glands make too little cortisol and too many androgens. This type of CAH does not result in aldosterone deficiency.

Other very rare types of CAH include 3-beta­hydroxy-steroid dehydrogenase deficiency, lipoid CAH, and 17-hydroxylase deficiency. They are not discussed here.

CAH can be categorized as classic or nonclassic types based on severity:

• Classic CAH is more severe than the nonclassic form. It can be life threatening in newborns if it is not diagnosed. Classic CAH can be caused by either 21-hydroxylase or 11-hydroxylase deficiency.
• Nonclassic CAH is sometimes called late-onset CAH. It is a milder form of the disorder that usually is diagnosed in late childhood or early adolescence. Sometimes, people have nonclassic CAH and never know it. This form of CAH is almost always caused by 21-hydroxylase deficiency.

Figure 1. Position of the adrenal glands and kidneys in the human body.

CAH is caused by changes (mutations) in one of several genes. These changes lead to deficiencies in 21-hydroxylase or, less commonly, 11-hydroxylase. Both of these are chemicals called enzymes. The adrenal glands need these enzymes to make proper amounts of the hormones: cortisol, aldosterone, androgens, and adrenaline.

Figure 2. Inheritance of an autosomal recessive disorder from carrier parents.

How is CAH inherited?

The genes for CAH are passed down from parents to their children. In general, people have two copies of every gene in their bodies. They receive one copy from each parent. For an infant to have CAH, both copies must have an error that affects an adrenal-gland enzyme.

CAH is an example of an autosomal (pronounced AW-tuh-soh-muhl) recessive disorder:

• Autosomal means the gene is not on the X chromosome or Y chromosome.
• Recessive means that both copies of the gene must have the error for the disease or disorder to occur.

If both parents have CAH, all of their children will also have it. If each parent carries one affected gene and one normal gene (called a "carrier"), there is a one-in-four chance of their child having CAH.

Classic CAH

Symptoms of classic CAH due to 21-hydroxylase deficiency (the most common type of CAH) can be grouped into two types according to their severity: salt wasting and simple virilizing (also called non-salt wasting).¹

Symptoms of classic CAH due to 11-hydroxylase deficiency are similar to those of simple virilizing CAH.² About two-thirds of people with classic 11-hydroxylase deficiency also have high blood pressure (hypertension).^2,3

Salt-wasting CAH

Salt-wasting CAH is the severe form of classic 21-hydroxylase deficiency. In this type of CAH, the adrenal glands make too little aldosterone, causing the body to be unable to retain enough sodium (salt). Too much sodium is lost in urine (thus the name, "salt-wasting"). If undiagnosed, symptoms of classic salt-wasting CAH appear within days or weeks of birth and, in some cases, death occurs.

Symptoms may include:

• Dehydration
• Poor feeding
• Diarrhea
• Vomiting
• Heart rhythm problems (arrhythmias)
• Low blood pressure
• Very low blood sodium levels
• Low blood glucose
• Too much acid in the blood, called metabolic acidosis (pronounced met-uh-BOL-ik as-i-DOH-sis)
• Weight loss
• Shock, a condition where not enough blood gets to the brain and other organs. Shock in infants with salt-wasting is called adrenal crisis. Signs include confusion, irritability, rapid heart rate, and/or coma.

Even when carefully treated, children with salt-wasting CAH are still at risk for adrenal crises when they become ill or are under physical stress. The body needs more than the usual amount of adrenal hormones during illness, injury, or physical stress. This means a child with CAH must be given more medication during these times to prevent an adrenal crisis.

Salt-wasting CAH also involves symptoms caused by low cortisol and high androgens. These symptoms may include:

• In female newborns, external genitalia can be ambiguous, i.e., not typical female appearing , with normal internal reproductive organs (ovaries, uterus, and fallopian tubes)
• Enlarged genitalia in male newborns
• Development of certain qualities called virilization (pronounced vir-uhl-uh-ZEY-shuhn) in boys or girls before the normal age of puberty, sometimes as early as age 2 or 3. This is a condition characterized by:
  • Rapid growth
  • Appearance of pubic and armpit hair
  • Deep voice
  • Failure to menstruate, or abnormal or irregular menstrual periods (females)
  • Well-developed muscles
  • Enlarged penis (males)
  • Unusually tall height as children, but being shorter than normal as adults
  • Possible difficulties getting pregnant (females)
  • Excess facial hair (females)
  • Early beard (males)
  • Severe acne
  • Benign testicular tumors and infertility (males)

Simple virilizing (non-salt wasting) CAH

Simple virilizing CAH is the moderate form of classic 21-hydroxylase deficiency. This type of CAH involves less severe aldosterone deficiency. Therefore, there are no severe or life-threatening sodium-deficiency symptoms in newborns. Like salt-wasting CAH, simple virilizing CAH involves too little cortisol and too much androgen. Female newborns typically have ambiguous genitalia, and young children typically display virilization.

Nonclassic CAH

Almost all cases of nonclassic CAH are caused by a mild 21-hydroxylase deficiency. Most symptoms of nonclassic CAH are related to increased androgens. Symptoms can show up in childhood, adolescence, or early adulthood.²

Symptoms of nonclassic CAH can include:

• Rapid growth in childhood and early teens but shorter height than both parents
• Early signs of puberty
• Acne
• Irregular menstrual periods (females)
• Fertility problems (in about 10% to 15% of women)
• Excess facial or body hair in women
• Male-pattern baldness (hair loss near the temples)
• Enlarged penis (males)
• Small testicles (males)

Some people have nonclassic CAH and never know it because the symptoms are so mild.^1,2,3,4,5,6

During Pregnancy

If a woman already has a child with CAH and becomes pregnant with the same partner, her fetus has a one in four chance of having CAH. For this reason, prenatal testing can be done for some forms of CAH. A health care provider checks for the disorder by using techniques called amniocentesis (pronounced am-nee-oh-sen-TEE-sis) or chorionic (pronounced kawr-ee-ON-ik) villus sampling.^1,2

• Amniocentesis. This involves inserting a needle into the womb, through the abdomen, to withdraw a small amount of fluid from the sac that surrounds the fetus. The procedure is usually done between the 15th and 20th week of pregnancy.
• Chorionic villus sampling. This is similar to amniocentesis. A health care provider inserts a needle into the womb, either through the abdomen or the cervix, and extracts a small piece of tissue from the chorionic villi (the tissue that will later become the placenta). This procedure is usually done between the 10th and 12th week of pregnancy.

After a health care provider takes a sample using one of these techniques, he or she will perform a genetic test on the sample. This test will reveal whether the fetus has a gene change that causes CAH.

Parents may also choose to wait until birth to have the newborn tested. Talking to their health care providers may help parents identify the option that is right for them.

At Birth

All U.S. states have neonatal screening for CAH. Infants who test positive need to have follow-up testing done to confirm the diagnosis. If, for some reason, the neonatal screening is negative but there is high suspicion for CAH (such as ambiguous genitalia), further evaluation is also indicated.

Later in Life

Newborns do not show symptoms of nonclassic CAH, and the test done on newborns does not detect nonclassic CAH. Nonclassic CAH is diagnosed in childhood or adulthood, when symptoms appear. To diagnose nonclassic CAH, a health care provider may:

• Ask whether family members have CAH.
• Do a physical exam.
• Take blood and urine to measure hormone levels.
• Do a genetic test to determine if the patient has the gene change that causes CAH.

An X-ray can help to diagnose CAH in children. Because some children with CAH grow too quickly, their bones will be more developed than normal for their age.³

Treatments for CAH include medication and surgery as well as psychological support.^1,2,3,4

Medication

• Classic CAH 
  
  Newborns with classic CAH should start treatment very soon after birth to reduce the effects of CAH. Classic CAH is treated with steroids that replace the low hormones.
  • Infants and children usually take a form of cortisol called hydrocortisone.
  • Adults take hydrocortisone, prednisone, or dexamethasone, which also replace cortisol.
  • Patients with classic CAH also take another medicine, fludrocortisone, to replace aldosterone.
  • Eating salty foods or taking salt pills may also help salt-wasters retain salt.⁵

The body needs more cortisol when it is under physical stress. Adults and children with classic CAH need close medical attention and may need to take more of their medication during these times. They may also need more medication if they:

• Have an illness with a high fever.
• Undergo surgery.
• Sustain a major injury.

People who have classic CAH need to wear a medical alert identification bracelet or necklace. To alert medical professionals in case of an emergency, the bracelet or necklace should read: "adrenal insufficiency, requires hydrocortisone." Adults or parents also need to learn how to give an injection of hydrocortisone if there is an emergency.

Patients with classic CAH need to take medication daily for their entire lives. If a patient stops taking his or her medication, symptoms will return.

The body makes different amounts of cortisol at different times in life, so sometimes a patient's dose of medication may be too high or too low. Taking too much medication to replace cortisol can cause symptoms of Cushing's syndrome. These include:

• Weight gain
• Slowed growth
• Stretch marks on the skin
• Rounded face
• High blood pressure
• Bone loss
• High blood sugar

It is important to alert the health care provider if these symptoms appear so that he or she can adjust the medication dose.

• Nonclassic CAH 
  
  People with nonclassic CAH may not need treatment if they do not have symptoms. Individuals with symptoms are given low doses of the same cortisol replacing medication taken by people with classic CAH.
  
  Symptoms of nonclassic CAH that signal that the patient may need treatment are:
  • Early puberty
  • Excess body hair
  • Irregular menstrual periods (females)
  • Infertility

It may be possible for patients with nonclassic CAH to stop medication as adults if their symptoms go away.

Surgery

• Classic CAH
  
  Girls who are born with ambiguous external genitalia may need surgery. For example, surgery is necessary if changes to the genitals have affected urine flow.
  
  Surgery for treatment of classic CAH should be done by an experienced surgeon who has expertise with this specific type of surgery. Parents may want to consider surgery for their child during infancy, or they may want to delay until later in childhood. Parents should work with their child's health care providers to determine the best timing of treatments.
  
  The Endocrine Society provides care recommendations on classic CAH , and can help parents find a health care provider who specializes in CAH . The American Association of Clinical Endocrinologists also offers a way to find an Association endocrinologist .
  
  Parents may also want to find a psychologist, social worker, or other mental health professional to support them in their decision making. 
• Nonclassic CAH
  
  CAH Girls with nonclassic CAH have typical genitals, so they do not need surgery.