Congenital Adrenal Hyperplasia

CAH is caused by mutations in genes that provide instructions for making enzymes needed to produce cortisol in the adrenal glands. Research published in the Journal of Clinical Endocrinology & Metabolism (2023) confirms that over 95% of CAH cases are due to a deficiency of the enzyme 21-hydroxylase. Because the adrenal glands cannot produce cortisol, the brain's pituitary gland sends a continuous signal (ACTH) to the adrenals to work harder. This causes the glands to grow and divert all available 'building blocks' into the production of androgens (male sex hormones).

Non-Modifiable Risk Factors

• Genetics: CAH is an autosomal recessive disorder, meaning a child must inherit two copies of the defective gene (one from each parent) to develop the condition.
• Ethnicity: Certain groups, including Ashkenazi Jews, Yupik Eskimos, and certain Mediterranean populations, have a higher prevalence of the genetic mutations associated with CAH.
• Family History: Having a sibling or parent with CAH or who is a known carrier significantly increases risk.

Modifiable Risk Factors

Because CAH is a purely genetic condition present from conception, there are no modifiable lifestyle risk factors (such as diet or smoking) that cause the disorder. However, environmental stress and illness can trigger an adrenal crisis in those already diagnosed.

According to the CDC (2024), the risk is highest for children of two carriers. If both parents carry a CAH gene mutation, there is a 25% chance with each pregnancy that the child will have the condition. Carrier screening is available for high-risk populations to determine the likelihood of passing on the trait.

CAH cannot be prevented if the genetic mutations are present. However, prenatal diagnosis is possible through chorionic villus sampling (CVS) or amniocentesis. In some cases, prenatal treatment (administering hormones to the pregnant mother) has been used to reduce virilization in female fetuses, though this remains specialized and must be discussed with a maternal-fetal medicine specialist.

The diagnostic journey typically begins with universal newborn screening in many countries, including all 50 U.S. states. If a screen is positive or if symptoms appear later in life, a series of biochemical and genetic tests are performed.

Healthcare providers look for signs of adrenal insufficiency or androgen excess. In infants, this includes checking for ambiguous genitalia or signs of dehydration. In older children and adults, the exam focuses on growth velocity, skin changes, and pubertal development.

• Blood Tests: The primary test measures levels of 17-hydroxyprogesterone (17-OHP). High levels of this precursor suggest a 21-hydroxylase deficiency. Electrolyte panels are used to check for low sodium and high potassium.
• ACTH Stimulation Test: This is the 'gold standard' for diagnosing non-classic CAH. A patient is given a dose of synthetic ACTH, and blood is drawn to see how the adrenal glands respond.
• Genetic Testing: Molecular analysis of the CYP21A2 gene can confirm the diagnosis and identify the specific mutation, which helps predict the severity of the disease.
• Imaging: Bone age X-rays are often used in children to determine if their skeleton is maturing too quickly due to excess androgens.

Diagnosis is confirmed when 17-OHP levels are significantly elevated (typically >1000 ng/dL in a stimulated state) alongside clinical symptoms of androgen excess or salt-wasting.

Conditions that can mimic CAH include:

• Polycystic Ovary Syndrome (PCOS): Often confused with non-classic CAH due to similar symptoms like acne and irregular periods.
• Adrenal Tumors: Can cause high androgen levels but are not genetic.
• Other Enzyme Deficiencies: Such as 11-beta-hydroxylase deficiency, which also causes CAH but typically presents with high blood pressure.

The primary goals of CAH treatment are to replace the hormones the body cannot produce and to suppress the overproduction of androgens. This ensures normal growth, development, and the prevention of life-threatening adrenal crises.

According to the Endocrine Society Clinical Practice Guidelines (2024), the standard of care is lifelong hormone replacement therapy. This approach mimics the body’s natural rhythm of hormone secretion and is adjusted based on the patient's age and life stage.

• Glucocorticoids: These replace the missing cortisol. They help the body respond to stress and signal the pituitary gland to stop overstimulating the adrenals. Common side effects include weight gain and, if dosed too high, slowed growth in children.
• Mineralocorticoids: These replace aldosterone in patients with the salt-wasting form. They help the kidneys retain sodium and maintain blood pressure. Side effects may include high blood pressure or swelling.
• Salt Supplements: Especially in infancy, extra sodium chloride may be prescribed to help maintain electrolyte balance.

In cases where standard therapy is insufficient to control androgen levels without causing glucocorticoid toxicity, providers may consider androgen blockers or aromatase inhibitors (to prevent early bone maturation). These are typically used in specialized pediatric endocrine settings.

• Surgery: For biological females with severe virilization of external genitalia, reconstructive surgery may be considered. Current clinical consensus emphasizes shared decision-making with parents and, when possible, involving the patient in later years.
• Adrenalectomy: In extremely rare, treatment-resistant cases, surgical removal of the adrenal glands may be performed, though this creates a permanent state of adrenal insufficiency.

Treatment is lifelong. Patients require regular blood tests to monitor hormone levels and frequent height/weight checks for children. 'Stress dosing'—increasing glucocorticoid intake during illness, fever, or surgery—is a critical component of management.

> Important: Talk to your healthcare provider about which approach is right for you.

For individuals with salt-wasting CAH, maintaining adequate sodium intake is vital. Research in the American Journal of Clinical Nutrition suggests that infants may require specific salt supplementation added to formula. For adults on long-term glucocorticoids, a diet rich in calcium and Vitamin D is recommended to support bone density, as steroid use can increase the risk of osteoporosis.

Most people with CAH can participate in all forms of exercise. However, during intense physical exertion or in extreme heat, those with salt-wasting forms must be careful to stay hydrated and may need extra salt. It is important to wear a medical alert bracelet during competitive sports.

Consistent sleep patterns help regulate the body's natural circadian rhythm, which is closely tied to cortisol production. Fatigue can be a sign of inadequate hormone replacement, so maintaining a regular sleep schedule is a key part of symptom management.

Physical and emotional stress increases the body's demand for cortisol. Evidence-based techniques such as mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT) can help patients manage the psychological burden of a chronic condition and reduce the physiological impact of stress.

While no supplement can replace missing hormones, some patients find that acupuncture or yoga helps manage the fatigue and stress associated with the condition. However, these should never replace prescribed hormone replacement therapy.

• Emergency Kits: Always keep an injectable hydrocortisone kit available for adrenal crises.
• School Coordination: Ensure teachers and school nurses understand the signs of an adrenal crisis and the need for immediate action.
• Psychosocial Support: Connect with support groups like the CARES Foundation to help children navigate the social aspects of the condition.

With early diagnosis and consistent medical management, the prognosis for individuals with CAH is generally excellent. According to a long-term study published in The Lancet Diabetes & Endocrinology (2022), most individuals with CAH have a normal life expectancy. However, they do face a higher lifetime risk of metabolic issues, such as obesity and insulin resistance, due to long-term steroid therapy.

• Adrenal Crisis: The most significant short-term risk, which can lead to shock and death if not treated immediately.
• Short Stature: If androgen levels are not well-controlled during childhood.
• Fertility Issues: Both men and women may experience challenges with conception, though many successfully have children with the help of an endocrinologist.

Management involves transitioning from pediatric to adult endocrinology. Adults need continued monitoring for bone health, cardiovascular risk, and reproductive function.

Success involves becoming an expert in one's own condition. This includes understanding 'stress dosing' rules and maintaining a strong relationship with an endocrinology team.

Contact your healthcare provider if you experience persistent fatigue, unexplained weight loss, darkening of the skin, or if you are planning a pregnancy. Any major illness or upcoming surgery requires a consultation to adjust medication dosages.