Congenital Adrenal Hyperplasia (CAH) is a group of inherited genetic disorders that affects the adrenal glands, which sit atop the kidneys and are responsible for producing several essential hormones, including cortisol and aldosterone. The condition arises from a deficiency in one of the enzymes required for hormone synthesis, which leads to an altered production pathway where certain precursor hormones build up and male sex hormones (androgens) are overproduced. While the severe, or classic, form is typically diagnosed in infancy through newborn screening, a milder presentation known as non-classic or late-onset CAH (NCAH) often remains undiagnosed until adolescence or adulthood. This article focuses on the diagnostic process for NCAH in adults.
Clinical Indicators for Testing
The decision to test an adult for non-classic Congenital Adrenal Hyperplasia is typically prompted by symptoms related to an excess of androgens, or male hormones. In women, the most common clinical sign is hirsutism, which is the growth of coarse, dark hair in a male-like pattern on the face, chest, or back. These symptoms often begin around puberty or in early adulthood.
Irregular or absent menstrual periods, known as oligomenorrhea or amenorrhea, are also frequent indicators that lead to suspicion of NCAH. Many women with the condition present with a clinical picture that closely mimics Polycystic Ovary Syndrome (PCOS), including signs like acne, androgenic alopecia (male-pattern hair thinning), and fertility difficulties. The presence of premature pubarche in childhood—the early development of pubic or armpit hair—is another historical detail that can raise suspicion. Specific testing is needed because these symptoms overlap significantly with other common endocrine disorders.
Initial Screening Procedures
The diagnostic process begins with a simple blood test to measure the basal, or unstimulated, level of 17-hydroxyprogesterone (17-OHP). This steroid hormone is a precursor in the pathway to making cortisol, and it accumulates when the enzyme 21-hydroxylase is deficient. Elevated levels suggest a block in the adrenal hormone production line.
For optimal accuracy, the blood sample should be drawn in the morning, as 17-OHP levels fluctuate throughout the day, following the natural circadian rhythm of the adrenal glands. A basal 17-OHP concentration greater than or equal to 2 nanograms per milliliter (ng/mL), or 6 nanomoles per liter (nmol/L), is often used as a screening threshold to warrant further investigation. Certain medications, such as glucocorticoids or oral contraceptives, may need to be temporarily discontinued before the test to avoid skewing the results. If the basal 17-OHP level is significantly high (e.g., greater than 10 ng/mL), the diagnosis of NCAH is highly likely, but a definitive test is typically still performed for confirmation.
The Definitive ACTH Stimulation Test
When the basal 17-OHP screening suggests a possible diagnosis, the next step is the definitive adrenocorticotropic hormone (ACTH) stimulation test, often called the Cosyntropin stimulation test. This procedure is considered the gold standard for confirming the diagnosis of NCAH. The test involves injecting a synthetic version of ACTH, a pituitary hormone that normally signals the adrenal glands to produce cortisol.
The procedure begins with a baseline blood draw to measure the initial levels of 17-OHP and sometimes cortisol. Immediately following this, a standard dose of synthetic ACTH, typically 250 micrograms (mcg) of cosyntropin, is administered intravenously or intramuscularly. The synthetic ACTH stimulates the adrenal glands, forcing them to work at their maximum capacity.
Subsequent blood samples are then drawn at specific intervals, commonly at 30 and 60 minutes after the injection, to measure the maximum stimulated rise in 17-OHP. In a person without CAH, the adrenal glands efficiently convert the 17-OHP precursor into cortisol, resulting in only a small increase. In NCAH, the partial enzyme deficiency causes a significant, exaggerated buildup of 17-OHP in response to the stimulation, which is the diagnostic hallmark of the condition.
Interpreting Results and Genetic Confirmation
The interpretation of the ACTH stimulation test hinges on the peak level of 17-OHP measured after the injection. A stimulated 17-OHP level greater than 30 nmol/L (equivalent to approximately 10 ng/mL) is the widely accepted cutoff used to confirm the diagnosis of Non-Classic CAH due to 21-hydroxylase deficiency. This threshold can vary slightly depending on the specific laboratory assay used.
Levels between 14 ng/mL and 30 ng/mL are often considered definitive for NCAH, while those in a lower, borderline range may necessitate further steps for a conclusive diagnosis. For cases with ambiguous or borderline biochemical results, genetic testing is often employed. This testing specifically looks for mutations in the CYP21A2 gene, which provides the instructions for making the 21-hydroxylase enzyme.
Identifying the specific gene mutation confirms the diagnosis and distinguishes NCAH from other conditions that mimic its symptoms. Genetic confirmation is particularly important for patients considering family planning, as it provides information for genetic counseling regarding the risk of passing on the condition. Once the diagnosis is confirmed through these hormonal and genetic tests, patients are typically referred to an endocrinologist for specialized management.