What is Congenital Adrenal Hyperplasia (CAH)?

From the Guidelines

Congenital adrenal hyperplasia (CAH) is a group of inherited genetic disorders affecting the adrenal glands, primarily caused by enzyme deficiencies that disrupt cortisol production, leading to overproduction of adrenal steroids, including androgens, and resulting in virilization in females and precocious puberty in males 1.

Key Characteristics of CAH

• Enzyme deficiencies block normal cortisol synthesis, leading to ACTH overproduction and accumulation of cortisol precursors that get diverted to androgen pathways
• Females with CAH are exposed to androgens during gestation and are typically born with some degree of genital virilization
• Postnatal exposure to androgens would also occur until adrenal hormone replacement therapy is begun
• Individuals with CAH are usually assigned the female sex and raised as girls, but may exhibit masculinized behavior and have a higher likelihood of bisexual or homosexual interests

Diagnosis and Treatment

• Diagnosis of CAH involves urine steroid profile, sequencing of steroidogenic genes, and measurement of very long-chain fatty acids
• Treatment typically involves lifelong glucocorticoid replacement, usually with hydrocortisone, and mineralocorticoid replacement with fludrocortisone for salt-wasting forms
• Patients require regular monitoring of growth, blood pressure, and hormone levels to adjust medication doses
• During illness, surgery, or other stressors, stress dosing of glucocorticoids is necessary to prevent adrenal crisis

Importance of Early Diagnosis and Treatment

• Failure to diagnose CAH can result in serious harm, including shock, hyponatremia, and hyperkalemia
• Early diagnosis and treatment can significantly improve outcomes and quality of life for individuals with CAH
• Proper management of CAH allows most patients to lead normal lives, though lifelong medical supervision is required 1.

From the Research

Definition and Causes of Congenital Adrenal Hyperplasia (CAH)

• Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition that leads to glucocorticoid deficiency and is the most common cause of adrenal insufficiency in children 2.
• CAH is caused by the deficiency of one of the enzymes involved in cortisol synthesis, with more than 95% of cases occurring as a result of defects in the gene encoding 21-hydroxylase (CYP21A2) 3.
• The 21-hydroxylase deficiency has been divided into classical and non-classical forms, with the classical form requiring replacement of both glucocorticoid and mineralocorticoid hormones to prevent salt wasting crisis and reduce excessive corticotropin 3.

Clinical Manifestations and Treatment

• CAH is characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands, leading to symptoms such as premature adrenarche, growth acceleration, hirsutism, and irregular menses 4.
• Treatment of CAH involves glucocorticoid replacement therapy, such as hydrocortisone, along with increased stress doses for acute illness, trauma, and procedures, as well as mineralocorticoid and salt replacement as necessary 4, 5.
• The goal of treatment is to prevent adrenal crises, achieve normal stature, optimal adult height, and normal puberty in children, and to prevent adrenal crises, ensure normal fertility, and avoid long-term consequences of glucocorticoid use in adults 2.

Diagnosis and Monitoring

• Diagnosis of CAH is typically made through newborn screening or later on through steroid analysis, with confirmation of 21-hydroxylase deficiency through genetic testing 6.
• Monitoring of CAH involves regular evaluation of growth rate, body weight, blood pressure, and physical examination, as well as biochemical measurements to assess the adequacy of glucocorticoid and mineralocorticoid treatment 3, 5.

Challenges and Future Directions

• Current treatment regimens for CAH have limitations, and there is a need for further research on optimal glucocorticoid replacement therapy, including the use of continuous slow-release or modified-release hydrocortisone preparations and continuous subcutaneous hydrocortisone infusion 2, 3.
• Additional challenges in the management of CAH include the risk of long-term comorbidities, such as cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects, as well as psychosocial and surgical considerations for individuals with genital differences 4, 5.