Congenital Adrenal Hyperplasia is a genetic disorder that impairs hormone production in the adrenal glands. To understand the condition, it is helpful to first understand what the adrenal glands do. The outer part of the adrenal gland, the cortex, produces three main types of steroid hormones from a common precursor, cholesterol:

1. Cortisol: A glucocorticoid often called the “stress hormone.” It is vital for maintaining blood sugar levels, blood pressure, and helping the body respond to stress, illness, and injury.
2. Aldosterone: A mineralocorticoid that regulates the body’s balance of salt (sodium) and water, which is essential for maintaining a healthy blood pressure.
3. Androgens: These are male sex hormones like testosterone. Both males and females produce androgens, which are important for growth and the development of male characteristics.

Producing these hormones is like a complex, multi-branched assembly line. In CAH, there is a genetic defect that causes a deficiency of one of the key enzymes—or “workers”—on this assembly line.

• The most common form of CAH, accounting for over 95% of all cases, is caused by a deficiency of the 21-hydroxylase enzyme.

This missing enzyme creates a major bottleneck in the factory. Assembly lines to produce cortisol and aldosterone are blocked. However, the raw materials continue to enter the factory. With their normal pathways blocked, these precursor materials are all shunted down the only remaining open path: the androgen production line. This results in two major problems:

1. A life-threatening deficiency of the essential hormones cortisol and aldosterone.
2. A massive overproduction of androgens (male sex hormones).

The term “hyperplasia” in the name refers to the fact that the adrenal glands themselves often become enlarged. This is because the pituitary gland in the brain senses the low cortisol levels and keeps sending out a strong signal (ACTH) telling the adrenal glands to work harder, causing them to grow.

In my experience, early diagnosis of CAH makes a world of difference. With the right treatment plan, kids can grow up healthy and thrive despite the hormonal challenges.

The most common form of CAH is caused by deficiency of the 21-hydroxylase enzyme. This enzyme deficiency is, in turn, caused by mutations in the CYP21A2 gene.

The CYP21A2 gene contains the precise genetic instructions the body uses to make the 21-hydroxylase enzyme. When this gene is mutated, the instructions are faulty, and the body produces an enzyme that is either non-functional or has severely reduced activity. Without a working 21-hydroxylase enzyme, the adrenal glands cannot produce adequate amounts of cortisol and aldosterone. Rarer forms of CAH are caused by mutations in other genes that code for different enzymes in the same steroid production pathway.

I’ve seen families completely unaware of CAH until newborn screening picks it up. Genetic counseling is key in helping them understand how and why it happens.

Congenital Adrenal Hyperplasia is an inherited genetic disorder. It is not contagious and cannot be acquired. It is passed from parents to their children through a specific inheritance pattern known as autosomal recessive inheritance.

This means:

• For a child to be born with CAH, they must inherit two copies of the mutated gene (e.g., CYP21A2), one from their mother and one from their father.
• The parents of an affected child are almost always unaffected carriers. A carrier has one normal copy of the gene and one mutated copy. Their one normal gene produces enough of the enzyme for them to be perfectly healthy and show no signs of the disorder. Most carriers are completely unaware of their genetic status.

When two carriers have a child together, there are three possible outcomes for each pregnancy:

• There is a 25% chance that the child will inherit a mutated gene from both parents and will be affected with CAH.
• There is a 50% chance that the child will inherit one mutated gene and one normal gene, and will be an unaffected carrier like their parents.
• There is a 25% chance that the child will inherit two normal genes and will be neither affected nor a carrier.

Because both parents must carry the same rare faulty gene, the chances of having a child with an autosomal recessive condition like CAH are higher in communities where marriage between close relatives, such as first cousins, is a common cultural practice. This is because related individuals have a greater likelihood of carrying the same inherited genetic traits.

I’ve seen siblings born years apart, one with classic CAH, another just a carrier. Genetic testing really helps parents plan ahead and understand recurrence risks.

Symptoms vary depending on the type (classic vs non-classic) and severity of the condition.

Classic CAH

This is the more severe form and is usually identified at birth or in early infancy. It is further divided into two types:

• Salt-Wasting CAH: This is the most severe form. The enzyme deficiency is so profound that the body produces almost no cortisol or aldosterone.
  • In female infants: The massive overproduction of androgens in the womb causes ambiguous genitalia at birth. The external genitals may not look clearly female or male. The internal reproductive organs (uterus, ovaries) are normal.
  • In male infants: The external genitals appear normal at birth. This can be dangerously misleading, as it means the condition may not be recognized until the baby develops a life-threatening crisis.
  • Adrenal Crisis: Within the first few weeks of life, infants with untreated salt-wasting CAH will develop a salt-wasting crisis. Due to the lack of aldosterone, they cannot retain salt, leading to severe dehydration, vomiting, poor feeding, lethargy, low blood sodium, high blood potassium, and eventually shock and death if not treated urgently.
• Simple Virilizing CAH: In this form, there is enough aldosterone production to prevent a salt-wasting crisis, but cortisol is still deficient and androgens are still overproduced.
  • In female infants: Ambiguous genitalia are present at birth.
  • In both boys and girls: If left untreated, the excess androgens will cause signs of early puberty, such as the development of pubic hair, rapid growth, and a deep voice, well before the normal age of puberty.

Non-Classic CAH (NCAH)

This is a much milder and more common form where the enzyme deficiency is only partial. Symptoms are not present at birth and typically appear in late childhood, adolescence, or early adulthood.

• In females: Symptoms can include irregular menstrual periods, hirsutism (excessive male-pattern hair growth), severe acne, and fertility problems.
• In males: They may have early puberty or may be completely asymptomatic and never be diagnosed.

What’s tricky about CAH is how symptoms range from subtle to life-threatening. In newborns, even slight delays in diagnosis can quickly turn into a salt-wasting crisis.

CAH is often detected through newborn screening, but additional tests are needed to confirm the diagnosis and assess severity.

• Newborn Screening: In many countries, every baby undergoes a routine blood test (a “heel prick”) 24 to 48 hours after birth to screen for a panel of serious but treatable genetic disorders. CAH is included in most of these panels. The test measures the level of 17-hydroxyprogesterone (17-OHP), which is the precursor chemical that builds up when the 21-hydroxylase enzyme is not working. An abnormally high 17-OHP level is a strong indicator of classic CAH.
• Clinical Diagnosis: In regions where universal newborn screening is not yet standard practice, the diagnosis often relies on a doctor recognizing the clinical signs, such as ambiguous genitalia in a newborn female or a “sick newborn” with symptoms of vomiting, dehydration, and lethargy in the first few weeks of life.
• Confirmatory Testing: A diagnosis suspected by screening or clinical signs is confirmed with further blood tests to measure levels of 17-OHP, cortisol, androgens, and electrolytes.
• Genetic Testing: A definitive diagnosis can be made by sequencing the CYP21A2 gene to identify the specific mutations. This is also essential for genetic counseling.

In practice, a high 17-OHP on newborn screening is usually the first clue. Quick follow-up testing can prevent dangerous complications, and give parents peace of mind.

There is no cure for CAH. The goal of treatment is to replace the missing hormones, prevent salt loss, support normal growth, and address fertility or sexual development issues.

1. Hormone Replacement Therapy

This is the cornerstone of management. The goal is to provide enough steroids to ensure normal growth and health while also suppressing the excess androgen production.

• Glucocorticoid Replacement: A form of cortisol, usually hydrocortisone for children, is given in daily divided doses to replace what the body cannot make.
• Mineralocorticoid Replacement: For individuals with the salt-wasting form, a medication called fludrocortisone is given to help the body retain salt and maintain a normal blood pressure. Infants may also need sodium chloride supplements.

2. Stress Dosing

This is a critical aspect of living safely with CAH. The body’s need for cortisol increases dramatically during times of physical stress, such as fever, a significant illness, surgery, or major injury.

• Patients and their families must be taught how to administer a “stress dose” of hydrocortisone (typically two to three times the usual daily dose) during these times to prevent a life-threatening adrenal crisis.
• Everyone with classic CAH must have an emergency hydrocortisone injection available at all times.

3. Surgical Management

For girls born with ambiguous genitalia due to high prenatal androgen exposure, feminizing genitoplasty may be considered. This is a complex surgical procedure performed by a specialized pediatric surgeon or urologist to create more typically female-appearing external genitalia. The decision and timing of this surgery involve extensive, sensitive discussions between the medical team and the family.

4. Lifelong Monitoring

Living with CAH requires regular follow-up with an endocrinologist to monitor growth, puberty, bone health, and hormone levels. Medication doses are adjusted throughout a person’s life based on these results.

Managing CAH is a lifelong journey, not a one-time fix. I always emphasize that with consistent medication and follow-up, kids with CAH can grow up strong, confident, and healthy.

Congenital Adrenal Hyperplasia is a complex inherited disorder that disrupts the body’s essential hormone production, leading to a dangerous deficiency of cortisol and aldosterone and an excess of androgens. The consequences of untreated classic CAH can be devastating, from the development of a fatal salt-wasting crisis in infancy to the challenges associated with ambiguous genitalia and early puberty. However, CAH is a treatable condition. With early diagnosis, ideally through newborn screening, and a lifelong commitment to careful hormone replacement therapy and proper management during times of illness, the life-threatening risks can be averted.

National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). (2021). Congenital Adrenal Hyperplasia (CAH). Retrieved from https://www.nichd.nih.gov/health/topics/cah

National Organization for Rare Disorders (NORD). (2023). Congenital Adrenal Hyperplasia. Retrieved from https://rarediseases.org/rare-diseases/congenital-adrenal-hyperplasia/

The CARES Foundation. (n.d.). What is CAH? Retrieved from https://caresfoundation.org/what-is-cah/