congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is an inherited disorder of steroid hormone production that primarily affects the adrenal glands and, secondarily, growth, blood pressure, and sexual development. It is caused by changes in the CYP11B1 gene, which provides instructions for the 11-beta-hydroxylase enzyme that helps make the hormones cortisol and aldosterone. Symptoms usually become obvious in infancy or early childhood; girls are often noticed at birth because of genital changes, while boys may present later with rapid growth or high blood pressure. The condition is considered rare, affecting approximately 1 to 9 per million people worldwide. Severity and symptoms vary widely between individuals.

The clinical picture reflects a shortage of cortisol and aldosterone combined with excess adrenal androgens. Endocrine and metabolic features are usually the first clues. Virtually all affected children have very low cortisol levels and markedly elevated 11-deoxycortisol, leading to episodes of low blood sugar, fatigue, or poor stress tolerance. At the same time, excess androgens drive rapid growth and early skeletal maturation; many children grow quickly in early childhood but may ultimately have short adult stature if treatment is delayed. Cardiovascular findings are prominent. Most individuals develop high blood pressure and low renin levels because of the accumulation of 11-deoxycorticosterone, a steroid with mineralocorticoid activity. Hypokalemia (low blood potassium) can accompany hypertension and may cause muscle weakness or cramps. Genital and reproductive features differ by sex. Females often have virilized or ambiguous genitalia at birth, such as clitoral enlargement or a partially fused labia. Males typically appear normal in the newborn period but may show early pubic hair, enlargement of the penis, or rapid growth in early childhood. Irregular menstruation, hirsutism, or reduced testicular size can become concerns in adolescence or adulthood. Other features seen in many, but not all, individuals include hyperpigmented skin, premature adrenarche or pubarche, and overall growth abnormalities. Not all individuals experience every symptom, and severity can differ even among siblings (variable expressivity).

This condition results from pathogenic variants in the CYP11B1 gene. The gene encodes the 11-beta-hydroxylase enzyme that converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone in the adrenal steroid pathway. When the enzyme is missing or markedly reduced, cortisol and aldosterone levels fall while precursor steroids build up and are diverted into androgen production, explaining both the hormone deficiencies and the androgen excess. Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is inherited in an autosomal recessive pattern. A child must receive two altered copies of CYP11B1, one from each parent, to be affected. Parents who each carry one altered copy (carriers) are typically healthy but have a 25 percent chance with every pregnancy to have an affected child. This condition is more common when parents share a common ancestor because relatives are more likely to carry the same rare genetic variant. Carrier testing may be particularly relevant for families with shared ancestry, and genetic counseling is recommended for relatives who may wish to understand their chances of having an affected child.

Currently, management focuses on replacing absent hormones, controlling excess androgens, and monitoring for complications. Glucocorticoid replacement therapy supplies the missing cortisol, helps suppress excess androgen production, and supports normal growth. Mineralocorticoid activity is often adequate because 11-deoxycorticosterone accumulates, but some individuals still need supplementation or careful salt balance monitoring. Antihypertensive treatment may be required to manage high blood pressure, and potassium levels are monitored to prevent or correct hypokalemia. Surgical consultation is sometimes considered for females with significant genital differences, ideally within a multidisciplinary team that includes endocrinology, urology or gynecology, psychology, and genetics specialists. Long-term management includes regular surveillance for potential complications. Blood pressure, growth velocity, bone age, electrolyte levels, and hormone profiles are typically checked at scheduled intervals to fine-tune therapy. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Families should work with an experienced multidisciplinary team, and genetic counseling offers guidance for family planning and carrier testing.

When diagnosed early and managed carefully, many individuals lead healthy, active lives, attend school, work, and have families. Outcomes depend on the timeliness of diagnosis, consistency of hormone replacement, and control of high blood pressure. Some people may experience reduced adult height or fertility challenges, while others have minimal long-term sequelae. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with endocrinology specialists familiar with congenital adrenal hyperplasia and to enroll in disease registries that track long-term health. Genetic counseling can assist with understanding inheritance and family planning options.