Nonclassic congenital adrenal hyperplasia (NCCAH) is a genetic condition affecting the adrenal glands, small organs above the kidneys. It affects the body’s ability to produce certain hormones. It is considered a milder form of congenital adrenal hyperplasia, with symptoms often appearing later in life, sometimes in adulthood. Because its presentation can be subtle and varied, NCCAH is sometimes overlooked or misdiagnosed.
Understanding Nonclassic Congenital Adrenal Hyperplasia
Nonclassic congenital adrenal hyperplasia is the most frequently inherited disorder affecting adrenal steroid synthesis. Its primary cause is a partial deficiency of the 21-hydroxylase enzyme, involved in adrenal hormone production. This enzyme shortage is due to a genetic change inherited from both parents.
The genetic basis for this condition is autosomal recessive, meaning an individual must inherit two copies of the mutated CYP21A2 gene, one from each parent, to develop NCCAH. This partial enzyme deficiency leads to a buildup of precursor hormones, such as 17-hydroxyprogesterone (17-OHP), as they cannot be converted into necessary hormones like cortisol and aldosterone. Consequently, the body often compensates by overproducing androgens, which are male sex hormones.
While cortisol production is mildly impaired in NCCAH, it is sufficient to prevent an adrenal crisis, a severe, life-threatening condition seen in more severe forms of CAH. This distinguishes nonclassic CAH from classic CAH, which involves a more profound enzyme deficiency and severe hormone imbalances, often presenting in infancy with ambiguous genitalia in females and potentially life-threatening salt-wasting crises. Unlike the classic form, nonclassic CAH does not progress to classic CAH in affected individuals.
Recognizing the Signs
The clinical presentation of nonclassic congenital adrenal hyperplasia is diverse, with symptoms varying widely in their onset and severity. Many individuals may experience mild symptoms or remain asymptomatic, often leading to a delayed diagnosis, sometimes not until early adulthood. Symptoms can also resemble other conditions, making diagnosis challenging.
In females, common manifestations include excessive hair growth (hirsutism) on the face, chest, and back. Irregular menstrual cycles, such as oligomenorrhea (infrequent periods) or amenorrhea (absent periods), are common. Severe and persistent acne is another common sign, along with fertility issues, often stemming from anovulation or ovarian problems. These symptoms frequently lead to NCCAH being confused with Polycystic Ovary Syndrome (PCOS).
Males with NCCAH may exhibit less obvious signs, sometimes undiagnosed unless genetic screening is performed for family planning. Potential indicators include premature adrenarche (pubic or armpit hair before age 9). An early growth spurt, often followed by shorter adult stature, may also occur. Severe acne and, in some cases, subfertility may also be present.
In children and adolescents, signs like premature adrenarche (onset of pubic or armpit hair before age 8 in girls or age 9 in boys) are important. Other indicators can include an accelerated growth velocity and advanced bone age, meaning bones appear more developed than expected for chronological age. The symptoms, if untreated, may become worse over time.
Diagnosis and Management
Diagnosing nonclassic congenital adrenal hyperplasia begins with measuring blood levels of 17-hydroxyprogesterone (17-OHP). Elevated levels of this precursor hormone can suggest a deficiency in the 21-hydroxylase enzyme. This initial test provides an important indicator for further investigation.
The ACTH (adrenocorticotropic hormone) stimulation test is considered the gold standard for confirming a diagnosis of NCCAH. During this test, synthetic ACTH is administered intravenously, and blood samples are taken before and after to assess adrenal gland response. In individuals with NCCAH, post-ACTH blood samples show significantly increased 17-OHP, unmasking the partial enzyme deficiency. Genetic testing for CYP21A2 mutations can further confirm the diagnosis and is valuable for family counseling. Other hormone tests, like measuring androgen levels, may also support the diagnosis.
Management for symptomatic individuals with nonclassic CAH primarily involves low-dose glucocorticoid replacement therapy, such as hydrocortisone or prednisone. This treatment suppresses excessive ACTH production by the pituitary gland, reducing androgen overproduction from the adrenal glands. For specific symptoms, other supportive therapies may be used.
For females experiencing hirsutism or menstrual irregularities, anti-androgen medications or oral contraceptives can be prescribed. Ongoing care includes regular monitoring with periodic blood tests to check hormone levels and follow-up appointments with an endocrinologist to adjust treatment. While there is no cure for NCCAH, the long-term outlook for individuals with this condition is generally positive with appropriate management.