Understanding 17 Alpha-Hydroxylase/17,20-Lyase Deficiency
17 alpha-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia that disrupts hormone production, leading to abnormal sexual development, high blood pressure, and low potassium levels.
Overview
17 alpha(α)-hydroxylase/17,20-lyase deficiency is a condition that impairs hormone production in the gonads (ovaries in females and testes in males) and the adrenal glands. The gonads direct sexual development before birth and during puberty and are essential for reproduction. The adrenal glands, located on top of the kidneys, regulate hormones that control salt levels and other vital functions.
This condition is part of a group of disorders known as congenital adrenal hyperplasias. It causes an imbalance of steroid hormones, leading to high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development. The severity of these features varies between the complete form (more severe) and the partial form (typically less severe).
Symptoms & Clinical Features
Disruptions to sexual development affect males and females differently:
Females (XX Chromosomes)
- Born with normal external female genitalia, but internal reproductive organs (such as the uterus and ovaries) may be underdeveloped.
- Complete form: Individuals do not develop secondary sex characteristics (such as breasts and pubic hair) and do not menstruate (amenorrhea).
- Partial form: Individuals may develop some secondary sex characteristics, but menstruation is typically irregular or absent.
- Both forms result in an inability to conceive (infertility).
Males (XY Chromosomes)
- Problems with sexual development lead to abnormalities of the external genitalia.
- Complete form: The most severely affected are born with characteristically female external genitalia and are generally raised as females. However, because they lack female internal reproductive organs, they experience amenorrhea and do not develop female secondary sex characteristics. They have testes, but they are abnormally located in the abdomen (undescended). In some cases, the external genitalia do not look clearly male or clearly female.
- Partial form: Affected males may have a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum).
- Both complete and partial forms result in infertility.
Frequency
This condition accounts for about 1 percent of all congenital adrenal hyperplasia cases. It is estimated to occur in 1 in 1 million people worldwide.
Causes
The condition is caused by mutations in the CYP17A1 gene, which provides instructions for making an enzyme involved in the formation of steroid hormones. These hormones include:
- Sex hormones (such as testosterone and estrogen), which are required for normal sexual development and reproduction.
- Mineralocorticoids, which help regulate the body's salt and water balance.
- Glucocorticoids, which help maintain blood sugar levels and regulate the body's response to stress.
The CYP17A1 enzyme performs two critical reactions: 17 alpha(α)-hydroxylase activity (important for glucocorticoids and sex hormones) and 17,20-lyase activity (integral to sex hormone production).
A deficiency in both enzyme activities causes the disorder. The remaining level of enzyme activity determines the severity:
- Complete form: Mutations result in an enzyme with very little or no activity. The loss of 17α-hydroxylase activity impairs glucocorticoid production, leading instead to an excess of salt-regulating mineralocorticoids, which causes hypertension and hypokalemia.
- Partial form: Mutations allow some reduced level of enzyme activity.
- In both forms, the loss of 17,20-lyase activity impairs sex hormone production, disrupting reproductive system development and preventing the normal onset of puberty.
Inheritance
This condition is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have mutations. The parents of an affected individual each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition.
Other Names for This Condition
- 17-alpha-hydroxylase deficiency
- 17-alpha-hydroxylase-deficient congenital adrenal hyperplasia
- Adrenal hyperplasia V
- Combined 17 alpha-hydroxylase/17,20-lyase deficiency
- Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
- Congenital adrenal hyperplasia type 5
- Deficiency of steroid 17-alpha-monooxygenase