Nonclassic congenital adrenal hyperplasia (NCCAH) is a mild, late-onset genetic disorder affecting the adrenal glands, which are situated atop the kidneys. In NCCAH, a genetic mutation impairs the ability to produce the hormone cortisol efficiently. This distinguishes it from the more severe, classic forms of congenital adrenal hyperplasia (CAH) that are identified at birth.
Unlike classic CAH, symptoms of NCCAH often do not appear until late childhood or adolescence. The condition causes the body to overproduce male hormones, called androgens, which leads to a wide spectrum of symptoms, though some individuals remain entirely asymptomatic. NCCAH is one of the most common autosomal recessive disorders.
Symptoms and Presentation
The clinical features of NCCAH stem from an excess of androgen hormones and can vary significantly. Many individuals, particularly males, may have no noticeable symptoms and are only identified after a family member is diagnosed. For many, signs first become apparent during the hormonal shifts of puberty.
In females, symptoms are often more pronounced, leading to a higher rate of diagnosis. A common early sign is premature pubarche, the development of pubic hair before age eight. Later, women may experience persistent acne, hirsutism (coarse hair growth on the face, chest, and back), and female-pattern hair loss.
Menstrual irregularities are another frequent complaint, including oligomenorrhea (infrequent periods), which can contribute to fertility challenges. Because these symptoms overlap with conditions like polycystic ovary syndrome (PCOS), a careful diagnostic process is required.
In males, NCCAH is often asymptomatic or presents with subtle signs. Some boys may show early puberty, such as the appearance of pubic hair, and a rapid childhood growth spurt. This can lead to premature fusion of the growth plates, resulting in a shorter final adult height. While most men experience no further symptoms, some may have acne or, in rare cases, fertility problems.
Genetic Origins and Hormonal Imbalance
Nonclassic congenital adrenal hyperplasia is an autosomal recessive disorder, meaning an individual must inherit a mutated gene from both parents. The most common gene implicated is CYP21A2, which provides instructions for making the enzyme 21-hydroxylase.
The genetic mutations in NCCAH cause a partial deficiency of this enzyme. This impairment disrupts hormone production, as the glands struggle to convert a precursor molecule, 17-hydroxyprogesterone (17-OHP), into cortisol. Cortisol helps the body respond to stress and illness.
With the pathway to cortisol partially blocked, the raw materials are shunted into an alternative route, leading to the overproduction of androgens. This excess of male hormones drives the clinical symptoms of NCCAH. The level of enzyme deficiency dictates the severity of the androgen excess and the resulting symptoms.
The Diagnosis Process
The diagnosis begins with a blood test to measure the baseline level of 17-hydroxyprogesterone (17-OHP), as symptoms can mimic other conditions. For women, this test is best performed in the morning during the first half of the menstrual cycle (the follicular phase) because levels can fluctuate.
If the initial 17-OHP level is elevated, the next step is the ACTH stimulation test, the gold standard for confirmation. This test measures a baseline 17-OHP level before a synthetic version of adrenocorticotropic hormone (ACTH) is given intravenously. Blood is drawn again after 60 minutes, and a significantly exaggerated 17-OHP response confirms the enzyme deficiency.
In situations like family planning or when hormone tests are ambiguous, genetic testing can be used. This analysis examines the CYP21A2 gene to identify the specific mutations. Confirming the genetic basis provides clarity and helps in counseling family members who may also carry the gene.
Management and Treatment Approaches
Management of NCCAH is individualized based on symptoms and personal goals. Treatment is not always required; if an individual is asymptomatic or has very mild symptoms that are not bothersome, observation and regular monitoring may be sufficient.
When treatment is initiated, it is tailored to specific symptoms. For issues like irregular periods, hirsutism, or rapid bone maturation in childhood, low-dose glucocorticoids are the primary treatment. Medications like hydrocortisone or prednisone suppress the adrenal gland’s overproduction of androgens.
For women whose primary concern is hirsutism or acne, other therapies like anti-androgen medications or oral contraceptives may be used. These can be used with or instead of glucocorticoids to manage the cosmetic effects of androgen excess. For women with NCCAH who wish to become pregnant, glucocorticoid treatment can help restore regular ovulation and improve fertility.