congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency

Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency is an inherited disorder of steroid hormone production that primarily affects the adrenal glands and, in males, the development of external genitalia. Variants in the HSD3B2 gene disrupt an enzyme needed to make cortisol, aldosterone, and androgens, leading to hormonal imbalances that can present in the newborn period or later in childhood. Because fewer than one in a million people are affected, many clinicians may never encounter a case. Both boys and girls can be affected, but undervirilization of male genitalia and salt-wasting crises often draw early medical attention. Severity and symptoms vary widely between individuals, even among siblings.

The condition has a spectrum of presentations. Early or presenting features often include poor feeding, vomiting, dehydration, low blood pressure, and electrolyte disturbances such as hyponatremia and hyperkalemia that reflect cortisol and aldosterone deficiency. Many newborn males have ambiguous genitalia ranging from micropenis to severe perineoscrotal hypospadias, while females may have mild genital ambiguity or appear typical at birth. Hormonal studies frequently show markedly elevated dehydroepiandrosterone-sulfate, 17-hydroxypregnenolone, and other precursor steroids. Over time, persistent adrenal insufficiency can lead to excess adrenocorticotropic hormone, skin hyperpigmentation, and episodes of low blood sugar. Some affected males experience decreased fertility or gynecomastia during adolescence. Individuals who do not have the classic salt-wasting form may come to medical attention later with premature pubarche or growth problems. Not all individuals experience all features, and the clinical spectrum ranges from mild non-salt-wasting disease to life-threatening neonatal crises.

The disorder is caused by pathogenic variants in the HSD3B2 gene. This gene encodes the type II 3-beta-hydroxysteroid dehydrogenase enzyme, which is essential for converting precursor molecules into cortisol, aldosterone, and testosterone. When the enzyme is deficient, the adrenal glands cannot produce adequate amounts of these hormones, and excess precursor steroids accumulate. It is inherited in an autosomal recessive pattern. An individual must receive one altered copy of HSD3B2 from each parent to be affected, so parents who carry a single variant typically have no symptoms. Each pregnancy in such a couple carries a 25 percent chance of producing an affected child, a 50 percent chance of having a carrier child, and a 25 percent chance of having an unaffected, non-carrier child. This condition is more common when parents share a common ancestor because related parents are more likely to carry the same rare genetic variant. Genetic counseling can help families understand carrier testing options and reproductive choices. Even within the same family, the type and severity of symptoms can vary considerably (variable expressivity).

Currently, management focuses on lifelong hormone replacement tailored to each individual’s needs. Glucocorticoid therapy supplies the missing cortisol and helps suppress excess adrenal hormone precursors, while mineralocorticoid supplementation and salt intake correct aldosterone deficiency and prevent dehydration and electrolyte imbalances. Infants in salt-wasting crisis require prompt fluid resuscitation and hormone replacement in the hospital. Surgical consultation may be considered for individuals with significant genital ambiguity, and fertility specialists may assist adolescent and adult males who experience reproductive challenges. Care is best coordinated through a multidisciplinary team that includes pediatric or adult endocrinologists, urologists or gynecologists familiar with disorders of sex development, mental health professionals, and genetic counselors. Regular surveillance is an essential part of long-term care, with periodic monitoring of growth, development, blood pressure, electrolytes, and hormone levels to adjust medication dosages and detect emerging complications early. Families should discuss emergency "stress-dose" plans for illness or surgery with their healthcare providers.

When diagnosed promptly and treated with appropriate hormone replacement, many individuals grow and develop well and can lead active lives. Delayed diagnosis or inadequate treatment, however, can result in life-threatening adrenal crises or long-term health issues such as poor growth and reduced fertility. Outcomes described in medical literature continue to evolve as standards of care improve. Individual experiences with this condition differ significantly, and long-term outlook depends on factors such as the severity of the enzyme deficiency, adherence to therapy, and access to experienced specialists. Families often find it helpful to connect with endocrinologists experienced in congenital adrenal hyperplasia and to seek genetic counseling for guidance on family planning and support resources.