Congenital Adrenal Hyperplasia (CAH) is a group of inherited genetic disorders affecting the adrenal glands, which are small organs situated above the kidneys. These disorders disrupt the body’s ability to produce specific hormones necessary for normal function. Late Onset Congenital Adrenal Hyperplasia (LOCAH), also known as non-classic CAH, is the milder, more common form of this condition, with symptoms typically appearing later in childhood or adulthood.
Understanding the Underlying Cause
The adrenal glands synthesize three main classes of steroid hormones: glucocorticoids (like cortisol), mineralocorticoids (like aldosterone), and androgens (sex hormones). LOCAH is primarily an autosomal recessive disorder, meaning an individual must inherit a mutated gene from each parent. In over 90% of cases, the underlying cause is a partial deficiency of the enzyme 21-hydroxylase, encoded by the CYP21A2 gene.
This enzyme is necessary for the adrenal glands to convert precursor molecules into cortisol and aldosterone. When 21-hydroxylase is partially defective, cortisol production is slightly impaired. This signals the pituitary gland to release excessive adrenocorticotropic hormone (ACTH). High ACTH levels overstimulate the adrenal glands, causing a buildup of precursor hormones that cannot be converted to cortisol or aldosterone. These precursors are shunted toward the pathway that produces androgens, leading to an overproduction of male sex hormones.
The level of enzyme activity differentiates LOCAH from the severe, classic form of CAH. Unlike the classic form, which involves a near-total enzyme deficiency and causes life-threatening adrenal crises shortly after birth, LOCAH retains enough enzyme function to produce sufficient cortisol and aldosterone under normal conditions. This residual activity prevents the severe salt-wasting and neonatal complications seen in classic CAH. Because the enzyme defect is partial, symptoms of androgen excess are delayed, often not manifesting until the hormonal changes of puberty or young adulthood.
Recognizing the Symptoms in Adults and Children
The manifestations of LOCAH are highly variable; some individuals remain completely asymptomatic, while others experience noticeable effects of androgen excess. Because symptoms often overlap with other conditions, LOCAH can be difficult to diagnose. The hormonal imbalances typically begin to express themselves in late childhood or around the time of puberty.
Symptoms in Females
In adolescent and adult females, the most common sign is hirsutism—the growth of coarse, dark hair in a male-like pattern, such as on the upper lip, chin, and chest. Many women also struggle with severe acne unresponsive to standard dermatological treatments. Excess androgens frequently interfere with the normal ovarian cycle, leading to menstrual irregularities such as oligomenorrhea (infrequent periods) or amenorrhea (absence of periods).
The hyperandrogenism and resulting menstrual dysfunction often lead to a misdiagnosis of Polycystic Ovary Syndrome (PCOS), a condition with similar symptoms. LOCAH is distinguished from PCOS by the underlying hormonal and genetic cause, though the two conditions can coexist. The hormonal disruption can also contribute to fertility challenges.
Symptoms in Males
Symptoms in males are often less pronounced or may be entirely absent, as the effects of excess androgens are less noticeable in a system already dominated by male sex hormones. Some men may experience chronic or severe acne and early-onset male-pattern balding. A less common, but specific, long-term complication is the development of benign masses in the testicles called Testicular Adrenal Rest Tumors (TARTs).
Symptoms in Children
In children, the signs of LOCAH usually involve premature pubertal development, known as precocious pubarche. This is characterized by the premature appearance of pubic or axillary (underarm) hair before the age of eight in girls or nine in boys. The excess androgens can cause an accelerated growth rate, making the child taller than their peers. However, this growth spurt is typically short-lived because androgens cause the bone growth plates to fuse earlier than normal, ultimately leading to a shorter final adult height.
Navigating the Diagnostic Procedures
Diagnosis of LOCAH requires careful evaluation beyond standard hormone testing due to the mild and intermittent nature of the enzyme deficiency. The initial step involves a blood test to measure the baseline level of 17-hydroxyprogesterone (17-OHP), the precursor hormone that builds up when 21-hydroxylase is defective. Because LOCAH is a milder form, basal 17-OHP levels may be only mildly elevated or even within the normal range, especially when measured later in the day.
To overcome this diagnostic challenge, the adrenocorticotropic hormone (ACTH) stimulation test is the gold standard for confirming LOCAH. This procedure involves drawing a baseline blood sample for 17-OHP measurement, followed immediately by an injection of synthetic ACTH. The synthetic ACTH rapidly challenges the adrenal glands to produce cortisol and other hormones.
A second blood sample is taken, typically 60 minutes after the injection, to measure the “stimulated” level of 17-OHP. In a person with LOCAH, the partially deficient enzyme cannot efficiently process the surge of precursor hormones, resulting in a dramatic rise in 17-OHP levels. A stimulated 17-OHP level \(\ge\)30 nmol/L is consistent with a diagnosis of non-classic CAH. Genetic testing can also identify specific mutations in the CYP21A2 gene, confirming the diagnosis, though it is often reserved for complex cases or family planning.
Treatment and Long-Term Management
The management of LOCAH is highly individualized, as asymptomatic individuals generally do not require treatment. The decision to initiate therapy depends primarily on symptom severity, particularly in women experiencing significant hirsutism, menstrual issues, or infertility. The main goal of treatment is to suppress the excessive production of androgens by the adrenal glands.
The primary treatment involves low-dose glucocorticoids, such as prednisone or dexamethasone. These medications replace the body’s natural cortisol and suppress the release of ACTH from the pituitary gland. By lowering ACTH levels, the adrenal glands are less stimulated, which reduces the overproduction of androgens.
For women, treatment for hyperandrogenism often includes anti-androgen medications, such as spironolactone (which blocks the effect of androgens at the tissue level), or oral contraceptives containing estrogen. These medications help control symptoms like acne and hirsutism and regulate menstrual cycles. Regular monitoring by an endocrinologist is necessary to ensure hormone levels are balanced, preventing both the effects of androgen excess and potential side effects, like bone density loss from prolonged steroid use.