Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency

This condition is a rare developmental defect that affects the adrenal glands and sexual development during embryogenesis. It is caused by pathogenic variants in the CYP11A1 gene, which plays a critical role in the production of steroid hormones. Affected individuals typically present early in life with severe salt-wasting adrenal insufficiency and ambiguous or female external genitalia despite having a 46,XY karyotype, although milder cases may manifest later with a range of genital appearances. The condition is very rare, affecting fewer than 1 in 1,000,000 people.

The clinical presentation is marked by early-onset adrenal insufficiency characterized by salt wasting, with low levels of cortisol, mineralocorticoids, and androgens leading to electrolyte imbalances such as elevated potassium and low sodium. Individuals with a 46,XY karyotype often display ambiguous or feminized external genitalia, although in milder forms, genital development may range from typical male to female. Not all individuals experience all features, and severity varies considerably.

The condition is caused by mutations in the CYP11A1 gene, which encodes the cholesterol side-chain cleavage enzyme, also known as p450scc. This enzyme is essential for the synthesis of steroid hormones in the adrenal glands. When the gene is altered, the resulting deficiency disrupts adrenal hormone production and interferes with normal sexual development in individuals with a 46,XY karyotype. Inheritance details are not specified in the current data, and genetic counseling is recommended to help families understand the implications of the genetic findings.

Currently, management focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for this condition. Treatment is individualized and typically involves a multidisciplinary team to address the endocrine imbalances as well as to support overall development and well-being. Supportive care may include hormone replacement therapy to manage adrenal insufficiency and monitoring of electrolyte levels, while additional specialists help manage any emerging complications. Patients should discuss treatment options with their healthcare team to determine the most appropriate approach for their circumstances, and genetic counseling is advised.

The long-term outlook for individuals with this condition varies widely, with outcomes largely dependent on the severity of adrenal insufficiency and the timeliness of appropriate care. With current standards of care, many individuals receive interventions that help manage symptoms effectively, though lifelong medical follow-up is often required. Outcomes described in medical literature continue to evolve as standards of care improve, and it is important to remember that the clinical course can range from stabilization after initial challenges to later complications in some individuals. Families often find it helpful to connect with genetic counselors and specialists experienced in endocrine and developmental disorders for ongoing guidance.