Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia is a group of inherited conditions that affect the adrenal glands and their ability to produce vital hormones, requiring lifelong management to maintain health and prevent serious complications.

Table of contents

• What is Congenital Adrenal Hyperplasia?
• The Adrenal Glands
• Types of Congenital Adrenal Hyperplasia
• Symptoms and Signs
• How CAH is Diagnosed
• Treatment Options
• Living with CAH
• Potential Complications

21-Hydroxylase Deficiency, 21-OH deficiency, adrenogenital syndrome, AG syndrome, Attenuated CAH, c-21-hydroxylase deficiency, congenital adrenocortical hyperplasia, CAH, Congenital Adrenal Hyperplasia (11βMonooxygenase Deficiency), Late-onset CAH, Salt-losing CAH, Virilizing Adrenal Hyperplasia

What is Congenital Adrenal Hyperplasia?

Congenital adrenal hyperplasia is the medical name for a group of genetic conditions that affect the adrenal glands^[1]. The word “congenital” means the condition is present from birth, “adrenal” refers to the glands involved, and “hyperplasia” means the glands become enlarged^[4].

If you have CAH, a gene change (a permanent alteration in the DNA sequence) results in a lack of one of the enzyme proteins (special proteins that help chemical reactions happen in the body) needed to make important hormones^[1]. Without this enzyme, your adrenal glands may not produce enough of certain hormones and may produce too much of others^[2].

Classic CAH affects as many as 1 in every 10,000 to 15,000 people living in the United States and Europe. Nonclassic CAH affects about 1 in every 100 to 200 people. Both classic and nonclassic CAH affect people worldwide^[2]. CAH occurs approximately once in every 15,000 people worldwide^[5].

There is no cure for congenital adrenal hyperplasia. But with proper treatment, most people who have CAH can lead full lives^[1].

• Adrenal glands
• Kidneys

The Adrenal Glands

The adrenal glands are a pair of walnut-sized organs above the kidneys. Although small, these glands control much of what happens in the body^[1]. You have one adrenal gland on top of each kidney^[2]. Each adrenal gland is made up of the medulla (middle) and the adrenal cortex (outer)^[5].

The adrenal glands produce important hormones your body needs to function properly. These include^[1][2]:

• Cortisol: This hormone controls the body’s response to illness or stress. It helps your body respond to illness, injury and stress. It’s also in charge of regulating your body’s blood pressure, energy levels and blood sugar levels.
• Aldosterone: This is a type of hormone called a mineralocorticoid. It helps your body maintain the correct levels of salt (sodium) and water. It also controls your blood pressure and blood volume.
• Androgens: These are male sex hormones such as testosterone. They help kick off puberty and play an important role in normal growth and development. These hormones are needed for growth and development in both males and females.

Types of Congenital Adrenal Hyperplasia

The two major types of congenital adrenal hyperplasia are classic CAH and nonclassic CAH^[1]. Two main types of CAH make up 95% of all cases^[2].

Classic Congenital Adrenal Hyperplasia

Classic CAH is the more serious form of the disease. This type is rarer and more serious. It’s usually found by tests at birth or in early infancy^[1]. It can cause adrenal complications such as shock and coma. If not found and treated early, it can be fatal. Diagnosis of classic CAH typically happens at birth^[2].

There are two subtypes of classic CAH^[2][4]:

Salt-wasting CAH: This is the most severe form of CAH. If you have salt-wasting CAH, your adrenal glands produce too little aldosterone. 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. Most babies with classic CAH have the salt-wasting form, where very little cortisol and aldosterone are made.

Simple-virilizing CAH: Simple-virilizing or non-salt wasting is a more moderate form of CAH. If you have this type, your aldosterone deficiency is less severe. There aren’t any life-threatening symptoms. But your body still doesn’t produce enough cortisol and makes too much androgen. The increase in androgens may cause symptoms related to sexual development. Babies with the simple-virilizing form of classic CAH also make very little cortisol but do make some aldosterone.

Nonclassic Congenital Adrenal Hyperplasia

Nonclassic CAH is the mildest form of CAH. This type is milder and more common. It may not be found until childhood or early adulthood^[1]. It usually doesn’t show up until later in childhood, adolescence or adulthood. You may or may not see symptoms. The overproduction of androgens may cause symptoms related to sexual development^[2].

Other Forms

Over 90% of people with CAH have a deficiency of an enzyme called 21-hydroxylase^[5]. There are several other rare forms of CAH, which each have different symptoms^[2]. These include CAH due to 11-beta-hydroxylase deficiency, 17 alpha-hydroxylase/17,20-lyase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, and Cytochrome P450 oxidoreductase deficiency^[4].

Symptoms and Signs

Symptoms of CAH vary. The symptoms depend on which gene is affected. They also depend on how greatly the adrenal glands lack one of the enzymes needed to make hormones. With CAH, the hormones that the body needs to work properly are thrown out of balance^[1]. CAH can cause various symptoms depending on the type and your sex^[2].

In Infants

In severe cases, symptoms can include poor weight gain, dehydration, or abnormal genital development in females^[12]. In female infants, symptoms can include atypical genitalia^[4].

In Children

Early signs may include rapid growth, early puberty, and short stature later in life^[12]. In salt-wasting CAH, the salt loss can cause acute dehydration, very low blood pressure (hypotension) and vomiting. As salt (sodium and chloride) and sugar (glucose) levels fall in the blood, potassium levels rise and if left untreated, a potentially life-threatening Adrenal Crisis (a medical emergency caused by dangerously low levels of cortisol) can result^[5].

In Adults

Fatigue, hormonal imbalances, irregular periods in females, and emotional challenges like anxiety are common^[12]. ‘Salt wasting’ and ‘non-salt wasting’ CAH can cause differences in early sexual development due to the body producing excess testosterone to compensate for the low levels of cortisol and aldosterone^[5].

How CAH is Diagnosed

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

Before Birth

Tests used to find CAH before birth in fetuses who are at risk for the condition include^[6]:

• Amniocentesis: This procedure involves using a needle to remove a sample of the fluid from the womb. This is called amniotic fluid. Then a lab checks the cells in the fluid.
• Chorionic villus sampling: This test involves removing cells from the organ that provides a fetus with oxygen and nutrients. This organ is called the placenta. A lab checks the sample of placenta cells.

Newborn Screening

In the United States and many other countries, newborns are routinely tested for 21-hydroxylase deficiency. The screening test is recommended during the first few days of life. This test can find the classic form of CAH. It doesn’t identify the nonclassic form^[6].

During screening, a special machine measures how much of a certain substance (called 17-OHP) is in your baby’s blood. This is a substance that builds up when the body does not produce enough cortisol. Babies with high levels of 17-OHP might have CAH due to 21-OHD^[4].

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].

Children and Adults

Tests to find CAH in children and adults include^[6]:

• Physical exam: A physical exam usually includes a check of blood pressure and heart rate. Symptoms also are reviewed.
• Blood and urine tests: These tests look for hormones made by the adrenal glands at levels outside the standard ranges. The tests also check the levels of minerals.

Treatment Options

While there’s no cure for CAH, treatment can help manage the symptoms and promote healthy function and development^[18]. Treatment includes various steroids to replace the hormones your body can’t make^[2].

Glucocorticoid Therapy

Many people with CAH are unable to make enough cortisol, the hormone that helps to regulate energy and stress levels. People with low levels of cortisol can also have high levels of androgens, which can lead to a number of severe symptoms. To help correct the effects of low cortisol levels, CAH may be treated using glucocorticoid therapy^[18].

Most children and adults with classic CAH require treatment with a glucocorticoid called hydrocortisone. This can address the hormone imbalance with a smaller risk of side effects. If treatment with hydrocortisone isn’t effective, your doctor may recommend another glucocorticoid called prednisone or dexamethasone^[8][18].

People with classic CAH are at risk of having a medical emergency known as an adrenal crisis. People under stressful conditions may need to take a higher dose of glucocorticoid than usual in order to avoid an adrenal crisis^[18].

Mineralocorticoid Therapy

It is advised that the addition of fludrocortisone and sodium supplementation to the treatment regimen is recommended for newborns and patients in early infancy^[8]. This helps to replace the missing aldosterone and maintain proper salt and water balance.

New Treatment Options

In December 2024, the FDA approved crinecerfont (Crenessity, Neurocrine Biosciences) as an adjunct to glucocorticoid replacement to control androgens for patients with CAH. This was the first new treatment approved for CAH in more than 70 years^[9]. Using a glucocorticoid-independent mechanism, crinecerfont decreases androgen overproduction, enabling the overall glucocorticoid dose to be reduced^[8].

Gene Therapy

Children with classic congenital adrenal hyperplasia have mutations in the CYP21A2 gene. This causes a deficiency of 21-hydroxylase, an enzyme essential for making cortisol and aldosterone. Gene therapy for classic CAH uses a viral vector to deliver functional copies of the CYP21A2 gene, so the adrenal glands can properly make 21-hydroxylase. This restores the ability to make cortisol and aldosterone. The gene therapy is delivered in one intravenous (IV) dose^[10].

Living with CAH

CAH 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 CAH^[12].

Medication Management

People with CAH must take daily life-long medication to replace the hormones which their adrenal glands don’t make^[5]. Some ideas for managing daily medicine include^[13]:

• Reminder alarms for when to take medication (e.g on a watch, smartwatch or mobile phone)
• Clearly labelled small plastic boxes or tins to hold medication supplies or emergency injection kits
• Pill boxes for handbags, bags, rucksacks
• Medical ID apps on certain smartphones to store your information and list of current medications

Sick Day Rules and Emergency Preparedness

People with CAH need extra steroids if they are ill. This can mean either an increase in the usual dose of tablets (for illness), or in some circumstances, the use of an emergency injection kit (in case of trauma or more severe illness)^[13].

An adrenal crisis can be a life-threatening situation for someone with CAH. Signs of an adrenal crisis include extreme weakness, a significant drop in blood pressure, drowsiness or mental confusion^[13]. Patients with dehydration, hyponatremia, or hyperkalemia and a possible salt-wasting form of adrenal hyperplasia should receive emergency treatment^[8].

Anyone who is steroid-dependent should carry a ‘steroid card’, to notify medics that steroid treatment must not be stopped and should be increased in illness or emergency. Medical ID jewellery (e.g. a bracelet or necklace/dog tag) helps to communicate medical information simply and quickly in an emergency to first responders, paramedics and doctors^[13].

Weight Management

CAH itself doesn’t necessarily affect your weight. But the medications you take to manage the condition can cause weight gain and make weight loss much more difficult^[14]. Glucocorticoids and mineralocorticoids are known to affect weight because they can increase your appetite. They can also make you retain water^[14].

Standard weight loss advice, like eating a well-balanced diet and exercising, still applies when you’re living with CAH. Exercise helps keep your heart healthy and your bones strong. A balanced diet helps make sure your body is getting all the vital nutrients it needs. Stress relief and good sleep allow your body and mind to take a much-needed pause^[14].

Mental Health

The experience of living with CAH, whether as a parent or an individual, can evoke a complex mix of emotions and challenges, influencing everything from daily routines to social connections and mental health^[16]. Feelings of anxiety and frustration are common, due to the physical changes that accompany the condition. The task of managing daily medications to treat CAH, along with the general fear of other possible health complications, can also affect mental health^[16].

Potential Complications

High levels of androgens, low levels of aldosterone, and low levels of cortisol can lead to the signs and symptoms of classic CAH^[4]. Common issues can include^[11]:

• Urinary incontinence in females
• Vaginal stenosis in females
• Clitoral pain in females
• Cosmetic concerns
• Testicular adrenal rest tumours in males

CAH can increase blood pressure, increase risk for atherosclerosis (a hardening of your arteries), and increase the risk for osteoporosis^[14].