Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
A rare CAH form with hypertension and sex hormone deficiency.
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of CAH caused by a mutation in the CYP17A1 gene. It leads to reduced synthesis of cortisol and sex hormones, along with increased mineralocorticoid production. Notable symptoms include mild cortisol deficiency, ambiguous genitalia in males or amenorrhea at puberty in females, and hypokalemic hypertension.
Quick Facts
- Incidence
- about 1 in 1,000,000 births
- Inheritance
- autosomal recessive
- Proportion of cah cases
- less than 5%
- Gene involved
- CYP17A1
Facts from the source article.
Pathophysiology
This rare form of congenital adrenal hyperplasia, making up under 5% of all cases, is caused by a lack of the enzyme 17α-hydroxylase, also known as CYP17A1. It follows an autosomal recessive inheritance pattern and occurs in roughly 1 out of every 1,000,000 births. Most cases involve a reduction in both the 17α-hydroxylase and 17,20-lyase functions of this enzyme. As with other CAH types, the body’s ability to make cortisol is compromised, which leads to high levels of ACTH and enlarged adrenal glands. The main clinical signs are an excess of mineralocorticoids and a shortage of sex hormones both before birth and during puberty. CYP17A1 normally works in steroid production, turning pregnenolone and progesterone into their 17α-hydroxy versions. This enzyme sits on the smooth endoplasmic reticulum of cells in the adrenal cortex and gonads that make steroids. Its two roles carry out three key chemical steps: as a 17α-hydroxylase, it converts pregnenolone to 17α-hydroxypregnenolone and progesterone to 17α-hydroxyprogesterone; as a 17,20-lyase, it changes 17α-hydroxypregnenolone into DHEA. The other possible lyase reaction, turning 17α-hydroxyprogesterone into androstenedione, happens so poorly in humans that it has no known effect. Different versions of the CYP17A1 gene produce enzymes with varying degrees of impairment, leading to a spectrum of health issues. For many years, the two enzyme activities were thought to come from separate genes, so medical texts described two distinct disorders: 17α-hydroxylase deficient CAH and a rarer condition called 17,20-lyase deficiency.
17,20-lyase deficiency
A very small number of people have reportedly had an abnormal allele resulting primarily in reduced 17,20-lyase activity rather than both hydroxylase and lyase activities. In these individuals, the defect causes isolated impairment of sex steroid synthesis, while mineralocorticoid and glucocorticoid levels remain normal. Normal aldosterone level is attributed to aldosterone being independent of the hypothalamus-pituitary axis feedback system and mainly controlled by serum potassium; thus hypertension is not expected. Normal cortisol level is explained by the strong negative feedback mechanism of cortisol on the hypothalamus-pituitary axis: the initial excess of cortisol from blocked sex steroid synthesis is rapidly corrected by decreased ACTH secretion, so there is no mineralocorticoid overproduction or adrenal hyperplasia. ACTH level remains in the normal range, though the reason is unclear. The sex steroid deficiency produces effects similar to 17α-hydroxylase deficiency. Severely affected genetic females are born with normal internal and external genitalia, with no clues until adolescence, when androgenic and estrogenic signs of puberty either fail to occur or are abnormal. Gonadotropins are high, the uterus is infantile in size, ovaries may contain enlarged follicular cysts, and ovulation may not occur even after estrogen replacement.
Treatment
For genetic females with this form of CAH, estrogen replacement is typically needed to start puberty, and periodic progestin is often required to regulate menstruation. Fertility tends to be low because reduced steroid production inside the ovaries does not support proper egg development and ovulation. Hypertension and excess mineralocorticoids are managed with glucocorticoid replacement, similar to other CAH types. The most challenging decisions involve genetic males with severe undervirilization. Many are raised as females, with nonfunctional testes removed surgically. If raised as males, a short course of testosterone in infancy can stimulate penile growth, hypospadias may be corrected surgically, and testes should be preserved through orchiopexy when possible. Testosterone replacement is necessary for puberty and must continue throughout adulthood.
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