Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases of adrenal steroidogenesis caused by mutations in genes encoding enzymes or cofactors involved in cortisol biosynthesis. For a detailed description of CAH variants see Chapter 5.9, here we briefly describe those variants that are associated with increased mineralocorticoid receptor activation. While the most frequent form of CAH, 21- hydroxylase deficiency (21OHD), is characterized by salt wasting and hypotension, 11β- hydroxylase deficiency (11OHD) and 17α- hydroxylase deficiency (17OHD), are associated with hypertension.
11β- Hydroxylase Deficiency
11OHD is the second most frequent cause of CAH, accounting for 2– 5% of cases (overall incidence 1 in 100 000– 200 000 live births). The enzyme 11β- hydroxylase (CYP11B1) catalyses the con version of 11- deoxycortisol to cortisol and DOC to corticosterone in the ZF. Defective cortisol biosynthesis results in ACTH secretion leading to accumulation of 11- deoxycortisol and DOC, which binds the MR with high affinity. Although a slightly less potent mineralocorticoid than aldosterone, the excessive production of DOC in 11OHD causes sodium retention, volume expansion and hypertension in 30– 60% of cases. Renin production is suppressed secondary to mineralocorticoid- induced sodium retention and volume expansion and aldosterone levels are decreased due to low serum potassium and low plasma renin. Because newborns are relatively resistant to mineralocorticoids, hypertension might not become apparent during the neonatal period. Increased ACTH secretion leads also to adrenal androgen excess resulting in fetal female virilization and precocious pseudo- puberty in boys. 11OHD is caused by inactivating mutations in the CYP11B1 gene located on chromosome 8q21 and is transmitted as an autosomal recessive trait. CYP11B1 is located in tandem with the highly homologous CYP11B2 gene. Opposite to FH- I, unequal crossing- over between those genes, where the CYP11B1 coding sequence is under the control of the CYP11B2 promoter responding to angiotensin II and not ACTH, also results in a phenotype of classic 11OHD. 11OHD treatment is based on cortisol replacement to normalize ACTH, which in turn removes the drive for overproduction of DOC, leading to remission of hypertension.
17α- hydroxylase Deficiency
17OHD is a rare form of CAH accounting for less than 1% of cases [81]. The enzyme 17α- hydroxylase (CYP17A1) is expressed in adrenal glands and gonads and catalyses 17α- hydroxylation of pregnenolone and progesterone as well as the 17,20 lyase reaction catalysing con version of 17- hydroxypregnenolone to dehydroepiandrosterone (DHEA) and, with less efficiency, that of 17- hydroxyprogesterone to androstenedione. 17OHD shifts steroidogenesis towards the mineralocorticoid pathway, with accumulation of corticosterone and DOC. Patients exhibit hypokalaemic hypertension, male undervirilization at birth in affected 46,XY individuals, primary amenorrhea in 46,XX patients, and hypergonadotropic hypogonadism in both sexes. 17OHD is caused by inactivating mutations in CYP17A1, located on the long arm of chromosome 10. To date, more than 100 mutations have been reported, 75% of which are missense mutations. 17OHD treatment is based on partial glucocorticoid replacement to reduce DOC production, antihypertensive management, mainly with MR antagonists, and sex steroid replacement according to age and sex of rearing.
