Adrenogenital Syndrome

Adrenogenital syndrome, also known as congenital adrenal hyperplasia, is a group of genetic disorders that affects the adrenal glands and their ability to produce vital hormones your body needs to function properly.

Congenital adrenal hyperplasia, CAH, Congenital adrenal cortical hyperplasia, Androgenital syndrome, Wilkins disease, Apert-Gallais syndrome, Adrenal virilism

C0302280

• Adrenal glands
• Kidneys

Table of contents

• What is adrenogenital syndrome?
• Types of the condition
• What causes adrenogenital syndrome?
• Signs and symptoms
• How is it diagnosed?
• Treatment options
• Living with adrenogenital syndrome

What is adrenogenital syndrome?

Adrenogenital syndrome is a genetic disorder that results from problems with steroid hormone (chemical messengers that control many body functions) production in the adrenal glands. These are two small, walnut-sized organs that sit on top of each kidney^[1][2].

Your adrenal glands make important hormones that help your body work properly. These include cortisol, which controls your body’s response to illness or stress and regulates blood pressure, blood sugar, and energy levels. They also produce aldosterone, which helps manage sodium and potassium levels in your blood and controls blood pressure. Additionally, they make androgens such as testosterone, which are sex hormones needed for growth and development in both males and females^[2][3].

The condition happens when a gene change results in a lack of one of the enzyme proteins needed to make these hormones. Most people with adrenogenital syndrome lack an enzyme called 21-hydroxylase. The adrenal glands need this enzyme to make enough cortisol and aldosterone. Because of low cortisol levels, the body stimulates the adrenal gland, which then produces more androgen. This results in an imbalance of these hormones^[4][5].

The pituitary gland (a small gland at the base of the brain) reacts to low cortisol by increasing secretion of a hormone called corticotropin, which in turn causes the adrenal glands to overproduce certain intermediary hormones which have testosterone-like effects^[1].

Types of the condition

There are two major types of adrenogenital syndrome, and they affect people differently^[2][3].

Classic congenital adrenal hyperplasia is the more serious and rarer form of the disease. It can cause adrenal complications such as shock and coma. If not found and treated early, it can be fatal. Diagnosis of classic form typically happens at birth. The body makes too little aldosterone and cortisol and too much androgen^[3][4].

Classic form has two subtypes. Salt-wasting is the most severe form, and it can cause life-threatening symptoms. Your adrenal glands produce too little aldosterone, and without enough aldosterone, your body can’t regulate the salt (sodium) levels in your blood. Low levels of aldosterone result in too much sodium being lost from your body through your urine. In addition, your body produces too little cortisol and makes too much androgen. It can be life-threatening without treatment^[3][4].

Simple-virilizing or non-salt wasting is a more moderate form. This type does not cause life-threatening symptoms. The body makes enough aldosterone to regulate sodium levels, but it still produces too little cortisol and too much androgen. The increase in androgens may cause symptoms related to sexual development^[3][4].

Nonclassic congenital adrenal hyperplasia is the mildest and most common form of the condition. The body produces enough aldosterone and cortisol, but too much androgen. It often is not diagnosed until later in childhood or adulthood. The person may not have any or only mild symptoms^[4][5].

Classic form affects as many as 1 in every 10,000 to 15,000 people living in the United States and Europe. Nonclassic form affects about 1 in every 100 to 200 people. Both forms affect people worldwide^[3].

What causes adrenogenital syndrome?

Adrenogenital syndrome is caused by mutations in genes responsible for producing enzymes that regulate hormone production in the adrenal glands. The condition is inherited in an autosomal recessive pattern, meaning both parents must carry a defective gene for their child to develop the condition. This means the traits are passed down from parent to child^[4][5].

The severity of the enzyme deficiency determines whether a person has classic (severe) or non-classic (milder) form. If you have a family history of adrenogenital syndrome, you may want to talk with your healthcare provider about having prenatal tests to check for the disorder in your unborn baby^[4][6].

Signs and symptoms

Symptoms will vary depending on the type of adrenogenital syndrome someone has and their age when the disorder is diagnosed^[4][5].

Females with classic form often have ambiguous genitalia (genitals that don’t clearly appear male or female) at birth and may be diagnosed before symptoms appear. Males have typical male genitalia at birth, even if they have a more severe form^[4][5].

In children with classic, salt-wasting form, several adrenal symptoms often develop within 2 or 3 weeks after birth. Electrolyte abnormalities generally take from a few days to 3 weeks to appear because the placenta maintains the fetal electrolytes while the baby is in the womb^[8]. These symptoms may include^[4][5]:

• Poor feeding or vomiting
• Diarrhea
• Dehydration
• Electrolyte changes (abnormal levels of sodium and potassium in the blood)
• Abnormal heart rhythm
• Low blood glucose
• Too much acid in the blood (metabolic acidosis)
• Weight loss
• Shock

Females with nonclassic form will usually have normal female reproductive organs (ovaries, uterus, and fallopian tubes). They may also have the following changes^[4][5]:

• Abnormal menstrual periods or failure to menstruate
• Early appearance of pubic or armpit hair
• Severe acne
• Excessive hair growth or facial hair
• Some enlargement of the clitoris

Males with nonclassic form often appear normal at birth. However, they may appear to enter puberty early. Symptoms may include^[4][5]:

• Deepening voice
• Severe acne
• Early appearance of pubic or armpit hair
• Enlarged penis but normal testes
• Well-developed muscles

Both males and females will grow rapidly during childhood, but be much shorter than normal as adults^[4][5].

How is it diagnosed?

Healthcare professionals may find adrenogenital syndrome before a baby is born, shortly after birth, or during childhood or later in life^[6].

Tests used to find the condition before birth in fetuses who are at risk include amniocentesis, which involves using a needle to remove a sample of the fluid from the womb, and chorionic villus sampling, which involves removing cells from the placenta (the organ that provides a fetus with oxygen and nutrients). A lab then checks these samples. Tests to confirm whether a baby has the condition are done after the baby is born^[6].

In the United States and many other countries, newborns are routinely tested for 21-hydroxylase deficiency as part of newborn screening tests. The screening test is recommended during the first few days of life. This is done with a heel stick to draw blood as part of the routine screenings done on newborns. This test can find the classic form but doesn’t identify the nonclassic form^[4][6].

In female infants whose outer genitals look very different than is typical, other tests can be done. The tests check structures inside cells that contain genes, called chromosomes, to identify genetic sex. Also, an ultrasound of the pelvis can find the presence of reproductive organs such as the uterus and ovaries^[6].

If a person has symptoms of any type of adrenogenital syndrome, the healthcare provider will do an exam and order certain tests. A physical exam usually includes a check of blood pressure and heart rate, and symptoms are reviewed. Common blood tests include^[4][6]:

• Serum electrolytes
• Aldosterone
• Renin
• Cortisol
• 17-hydroxyprogesterone

These tests look for hormones made by the adrenal glands at levels outside the standard ranges. Genetic tests can help diagnose or confirm the disorder, but they are rarely needed^[4].

Treatment options

There is no cure for adrenogenital syndrome. But with proper treatment, most people who have the condition can lead full lives^[2].

The goal of treatment is to return hormone levels to normal, or near normal. Treatment may include taking^[4][5]:

• Hydrocortisone to replace cortisol
• Fludrocortisone to replace aldosterone
• Salt supplements

Medicine should be taken daily. People may need additional doses of medicine during times of stress, such as severe illness or surgery. Lifelong monitoring is needed to ensure that proper hormone levels are maintained^[4][5].

Infants with ambiguous genitalia should be closely observed for symptoms and signs of salt wasting while a diagnosis is being established. Clinical clues include abnormal weight loss or lack of expected weight gain^[8].

Patients with dehydration, low sodium in the blood, or high potassium levels and a possible salt-wasting form should receive an intravenous bolus of isotonic sodium chloride solution over the first hour, as needed, to restore their intravascular volume and blood pressure. This dosage may be repeated if the blood pressure remains low. Glucose must be administered if the patient has low blood sugar and must be included in the rehydration fluid after the bolus dose to prevent low blood sugar^[8].

After samples are obtained to measure electrolyte, blood sugar, cortisol, aldosterone, and 17-hydroxyprogesterone concentrations, the patient should be treated with glucocorticoids based on suspected adrenal insufficiency. Treatment should not be withheld while confirmatory results are awaited because it may be life preserving^[8].

Steroids (such as hydrocortisone and fludrocortisone) used to treat the condition do not usually cause side effects such as obesity or weak bones, because the doses replace the hormones that the body cannot make. Steroids cannot be stopped suddenly because doing so may lead to adrenal crisis^[4].

In December 2024, the US Food and Drug Administration approved crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, to be used in combination with glucocorticoid replacement in adults and children aged 4 years or older, for androgen control in classic form. Using a glucocorticoid-independent mechanism, crinecerfont decreases androgen overproduction, enabling the overall glucocorticoid dose to be reduced^[8].

Gene therapy for classic form is also being investigated at some medical centers. This approach uses a viral vector to deliver functional copies of the affected gene, so the adrenal glands can properly make the missing enzyme. This restores the ability to make cortisol and aldosterone. The gene therapy is delivered in one intravenous dose. The ultimate goal of the gene therapy is to restore the adrenal glands’ normal function: responding to the body’s natural signals by releasing the right amount of hormones to react to stress, illness and daily living without additional medication^[10].

Living with adrenogenital syndrome

Adrenogenital syndrome requires consistent management to maintain hormone levels and prevent complications like adrenal crises, which can be life-threatening. Daily attention to medications, stress, and overall health is essential for living well with the condition^[11].

Standard weight loss advice, like eating a well-balanced diet and exercising, still applies when you’re living with adrenogenital syndrome. Exercise helps keep your heart healthy, which is especially important for people with the condition, as it can increase blood pressure and increase risk for hardening of your arteries. Exercise also helps keep your bones strong, lowering your risk for osteoporosis (weak bones). Aim for 150 minutes of moderate-intensity cardio exercise a week and two days of strength training^[14].

A balanced diet helps make sure your body is getting all the vital nutrients it needs to work its best. Choosing nutrient-dense foods can help to satisfy your appetite and keep you from overindulging in less-nutritious choices. Drinking lots of water is also important^[14][19].

Stress relief and good sleep allow your body and mind to take a much-needed pause. They’re healthy habits for anyone, but living with adrenogenital syndrome can be particularly stressful, which can be dangerous when your body can’t make enough of the hormone cortisol to help you manage it. Try yoga, breathing exercises or meditation. And talking with a therapist who understands your condition can make a difference^[14].

Some medications used to manage the condition can cause weight gain and make weight loss much more difficult. Glucocorticoids and mineralocorticoids are known to affect weight because they can increase your appetite and make you retain water. If weight management is becoming a problem, talk with your care team. Sometimes different medications or dosages can be considered. Some people benefit from switching from a long-acting glucocorticoid to a shorter-acting one^[14].

Many people describe the importance of talking to someone who’s actually been there and understands how you feel as a huge reassurance. Support groups, run by people who have been living with the condition for many years, provide support to people with adrenogenital syndrome and their families and friends, to increase awareness of the condition among the public and the medical profession, and to raise funds to support research^[13].