congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency

Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency is a very rare endocrine condition that affects adrenal steroid synthesis, leading to a combination of glucocorticoid deficiency, hypergonadotropic hypogonadism, and severe hypokalemic hypertension. The condition is caused by pathogenic variants in the CYP17A1 gene, which plays a critical role in the production of several steroid hormones. It typically presents in childhood or adolescence with hormonal imbalances affecting growth and sexual development. In terms of prevalence, this condition affects roughly 1 to 9 individuals per million, underscoring its rarity.

The clinical presentation is characterized primarily by severe high blood pressure due to an excess of mineralocorticoid precursors, alongside hormonal imbalances that result in glucocorticoid deficiency and sexual development abnormalities. Patients commonly exhibit features such as hypokalemia, abnormal responses to ACTH stimulation, elevated levels of certain adrenal hormones, and in many cases, primary amenorrhea in females or bilateral cryptorchidism in males. Additional hormonal findings include altered levels of gonadotropins and sex steroids, which contribute to the hypergonadotropic hypogonadism observed in this condition. Not all individuals experience every feature, and severity varies considerably.

This condition results from pathogenic variants in the CYP17A1 gene, which encodes an enzyme essential for the biosynthesis of steroid hormones. Disruption of this enzyme’s function impairs the production of glucocorticoids and sex steroids, while leading to an accumulation of mineralocorticoid precursors that contribute to hypertension. It is inherited in an autosomal recessive pattern, meaning that an individual must inherit two altered copies of the gene to be affected. This condition is more common when parents share a common ancestor, as both may be carriers of the rare variant; carrier testing may be particularly relevant for families with shared ancestry. Each child of two carrier parents has a 25% chance of being affected. Associated genes include CYP17A1.